MXPA01008618A - Small molecule modulators of g protein-coupled receptor six. - Google Patents

Abstract

Disclosed herein are small molecule modulators of the G protein-coupled receptor six, methods of making such compounds, and methods of using such compounds.

Description

MODULATORS OF SMALL MOLECULE OF SIX RECEIVER COUPLED OF PROTEIN G RELATED CASES This patent document relates to the Application for Patent of E U. 09 / 364,425 filed through Express Mail on July 30, 1999 which claims the benefit of commonly owned: (1) Provisional Patent Application Serial Number 60 / 094,879 filed on July 31, 1 998; (2) Provisional Patent Application Serial Number 60 / 106,300, filed on October 30, 1998; (3) Provisional Patent Application Serial Number 60/1 1 0,906 filed December 4, 1,998; (4) Provisional Patent Application Serial Number 60/121, 851 filed on February 26, 1999; (5) Provisional Patent Application Serial Number 60/1 73,850 filed on December 30, 1990; and (6) Provisional Patent Application Serial Number 60/1 74,428 filed on January 4, 2000. The description of each of the above patent documents is hereby incorporated by reference in its entirety. The priority benefit of the E Request. U. Ser. No. 09 / 364,425 and the Provisional Patent Applications (4), (5) and (6) above are claimed by it.

FIELD OF THE INVENTION The present invention relates to small molecule modulators of G protein coupled receptor 6 (GPR6); Preferably, the small molecule modulators are preferably selected for human GPR6; more preferably, the small molecule modulators are inverse agonists to human GPR6.

BACKGROUND OF THE INVENTION A. Protein G Coupled Receptors Coupled G protein (GPCR) receptors share a common structural motif. All these receptors have seven sequences of between 22 and 24 hydrophobic amino acids that form seven alpha helices, each of which encompasses the membrane. The transmembrane helices are joined by filaments of amino acids that have a longer loop between the fourth and fifth transmembrane helix on the extracellular side of the membrane. Another longer loop, composed mainly of hydrophilic amino acids, joins the transmembrane helices five and six on the intracellular side of the membrane. The carboxy terminus of the receptor lies intracellularly with the amino terminus in the intracellular space. It is thought that the loop joining the helices five and six, as well as the carboxy terminus, interact with the G protein. Currently, the Gq, Gs, Gi and Go proteins are G proteins that have been identified. Under physiological conditions, GPCRs exist in the cell membrane in equilibrium between two different states or conformations: an "inactive" state and an "active" state. A receptor in an inactive state is unable to bind to the intracellular transduction path to produce a biological response. Changing the conformation of the receptor to the active state allows the link to the transduction path and produces a biological response. A receptor can be stabilized in an active state by an endogenous ligand or an exogenous agonist ligand. Recent discoveries, which include but are not limited to, modifications to the receptor amino acid sequence, provide alternative mechanisms to other binders to stabilize active state information. These approaches effectively stabilize the receptor in an active state by stimulating the effect of a binder that binds to the receptor. Stabilization by such independent approaches of the binder is termed "constitutive receptor activation". A receptor for which the endogenous ligand is unknown or unidentified is referred to as an "orphan receptor". B. Traditional Selection of the Compound Generally, the use of an orphan receptor for selection purposes to identify compounds that modulate a biological response associated with such a receptor has not been possible. This is because the traditional "dogma" that considers the selection of compounds orders that the binder for the receptor be known, whereby compounds that bind competitively with the receptor, i.e., by interfering or blocking the binding of the natural binder with the receptor, are selected. By definition, then, this approach has no applicability with respect to orphan receivers. In this way, when ad to this dogmatic approach to the discovery of therapeutics, the subject, in essence, has taught and been taught to abandon orphan use at least until the natural binder is discovered for the receiver. The search for an endogenous ligand for an orphan receptor can take several years and cost millions of dollars. In addition, and given that there is an estimated 2,000 GPCRs in the human genome, most of which are orphan receptors, the traditional dogma punishes a creative approach to the discovery of therapeutics of these receptors. G-protein coupled receptor numbers, orphans are constitutively active in their endogenous state. GPR6 is a 362 amino acid homologue of GPR3; the endogenous ligand for GPR6 is unknown (Song, Z. H- et al., supra, see Figure 1 for reported amino acid sequence). Transcripts of GPR6 are reported to be abundant in the human putamen and to a lesser extent in the frontal cortex, hippocampus and hypothalamus (Heiber, M., et al., DNA and Cell Biology (1 995) 14 (1): 25; see Figure 1 for amino acid and nucleic acid sequences reported for GPR6). C. Obesity Recently, our current knowledge of human obesity has advanced dramatically. Previously, obesity was observed as a hostile behavior of inappropriate feeding in the middle of supplicant foods. Studies of animal models of obesity, biochemical alterations in both humans and animals, and the complex interactions of cultural and psychosocial factors that create receptivity to human obesity indicate that this disease in humans is multifaceted and deeply ingrained in human systems. biological In this way, it is almost certain that obesity has multiple causes and that there are different types of obesity. A growing number of children and adolescents are overweight.

Although not all overweight children will necessarily be overweight adults, the occurrence of obesity growth in childhood is likely to be reflected in increasing obesity in adult years. The high prevalence of obesity in our adult population and the likelihood that the nation of the future will be even more obese requires a re-examination of the health implications of this disease. See, Health Implications of Obesity, NIH Consens. Statemente Online 1985 Feb 1 1 -1 3; 5 (9): 1 -7. "Clinical obesity" is a measure of excess body fat relative to low body mass and is defined as a body weight more than 20% above ideal body weight. Recent estimates suggest that 1 in 2 adults in the United States are clinically obese, an increase of more than 25% over the past decades. Flegal MD, ei al., 22 Int. J. Obes. Relat. Metab. Disor. 39 (1998). Both conditions of overweight and clinical obesity are often a major health issue worldwide, particularly since clinical obesity is often accompanied by numerous complications, ie, hypertension and Type II diabetes, which at its may cause coronary artery disease, seizure, late stage complication of diabetes and premature death (See, for example, Nishina PM et al., 43 Metab 554 (1 994)). Although the etiological mechanisms that support obesity require additional classification, the net effect on such mechanisms leads to an imbalance between energy intake and consumption. Both genetic and environmental factors are probably included in the pathogenesis of obesity. These include excessive caloric intake, reduced physical activity, and endocrine and metabolic abnormalities. The treatment of conditions of overweight and clinical obesity through pharmaceutical agents is not only important with respect to the conditions themselves, but also with respect to the possibility of preventing other diseases that are associated with, for example, clinical obesity, as well as an increase in the positive feeling of "personality" that often accompanies those who are overweight or clinically obese or who find a significant reduction in body weight. Given the above discussion, it is apparent that the compounds that help in the treatment of such disorders would be useful and would provide an advance in both research and clinical medicine. The present invention addresses these, as well as other, important purposes.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to small molecule modulators of the GPR6 receptor. More preferably, the GPR6 modulators have inverse receptor agonist characteristics.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graphic representation of the results of the cyclic AMP analysis based on the cell that provides the comparative results for the constitutive signaling of GPR6 and GPR6: Fusion Protein. Figure 2 is a graphical representation of the results of a [3l3S] GTP? S analysis that provides the comparative results for constitutive signaling by GPR6 and GPR6: Fusion Protein. Figure 3 is a graphical representation of the results of a first selection of several candidate compounds against GPR6; the results for the compound "ARE 1 12" is provided in the H6 cavity. Figure 4 is a graphical representation of an IC 50 curve for the compound ARE 1 12 against the GPR6 receptor, indicated an ICso value of 0. 1 501 μM. Figures 5A, 5B and 5C provide graphical representations of the results of in vivo (IP) administration of ARE 1 12 in cumulative food intake (5A), water intake (5B) and body weight gain (5C) in private rats of food for 24 hours. Figures 6A, 6B and 6C provide graphical representations of the results of in vivo (IP) administration of ARE 1 12 in cumulative food intake (6A), water intake (6B) and body weight gain (6C) in rats not deprived of food. Figures 7A, 7B and 7C provide graphical representations of the results of in vivo administration (ICV) of ARE 1 12 in cumulative food intake (7A), water intake (7B) and body weight gain (7C) in private rats of food for 24 hours. Figure 8 provides a graphic representation of the results of ARE1 12 on locomotor activity in rats 16 hours after administration. Figures 9A and 9B provide graphical representations of the results of in vivo administration (oral-priming) of ARE1 12 in cumulative food intake in food deprived rats for 24 hours (9A) and in cumulative food intake in rats not deprived of food (9B). Figures 1A, 1B and 10C provide graphical representations of the results of in vivo administration (oral-priming) of structural analogs in cumulative food intake (10A), water intake (10B) and body weight gain (10C). ) in rats deprived of food for 24 hours. Figure 11 provides a graphic representation of the results of a daily repeated in vivo (PI) administration of ARE 1 12 in rats that show a long-term reduction in body weight without depriving them of food. Figure 12 provides a graphic representation of the results of in vivo (oral-priming) administration of ARE 1 12 showing a reduction in startle reflex in rats not deprived of food. DEFINITIONS The scientific literature that has been wrapped around the recipients has adopted a number of terms. For clarity and consistency, the following definitions will be used throughout this patent document. To the extent that these definitions conflict with other definitions for these terms, the following definitions will be controlled. ACTIVE INGREDIENT in the context of a "Composition Pharmaceutical "must mean a component of a Pharmaceutical Composition that provides the primary pharmaceutical benefit, as opposed to an" inactive ingredient "that would generally be recognized as not providing a pharmaceutical benefit AGONISTS must mean portions that activate the intracellular response when they bind to the recipient , or increase the binding of GTP to the membranes In the context of the invention described, a Pharmaceutical Candidate comprising a GPR6 Agonist can be used to increase body weight and / or affect the metabolism so that the recipient gains weight and / or maintain the weight, Such can be used in the context of disorders and / or diseases where weight loss is a component of the disease and / or disorder such as, for example, anorexia nervosa, cancer, AIDS cachexia, etc. PARTIAL AGONISTS must mean portions that activate the intracellular response when they bind to the recipient at a lower grade / measurement that e what the agonists do, or increases the binding of GTP to the membrane to a lesser degree / measurement than the agonists do. ANTAGONISTS must mean portions that bind competitively to the receptor at the same site as the agonists but that do not activate the intracellular response initiated by the active form of the receptor, and may thus inhibit intracellular responses by agonists or partial agonists. ANTAGONISTS do not decrease the intracellular baseline response in the absence of an agonist or partial agonist. COMPOSITE CANDIDATE in the context of the described invention, must mean a small molecule that is receptive to the selection technique. COMPOSITION should mean a material comprising at least two compounds or two components, for example, without limitation, a Pharmaceutical Composition comprising at least one Active Ingredient and at least one other component is a Composition. COMPOUND EFFECTIVENESS should mean a measurement of a compound's ability to inhibit or stimulate receptor functionality, as opposed to receptor binding affinity. ACTIVATION OF THE CONSTITUTIVE RECEIVER should mean stabilization of a receptor in an active state by means other than the binding of the receptor with its endogenous ligand or a chemical equivalent thereof. CONTACT or CONTACT must mean bringing at least two portions together, either in an in vitro system or in an in vivo system. ENDOGEN must mean a material that a mammal produces naturally. ENDOGEN in reference to, for example and without limitation, the term "receptor" should mean that it occurs naturally by a mammal (eg, without limitation, a human) or a virus. In contrast, the term NON-ENDOGEN in this context should mean that it is not produced naturally by a mammal (for example, and without limitation, a human) or a virus. For example, and without limitation, a receptor that is not constitutively active in its endogenous form, but when manipulated becomes constitutively active, is more preferably referred to herein as a "constitutively active, non-endogenous receptor". Both terms can be used to describe both "in vivo" systems and "in vitro" systems. For example, and not a limitation, in a selection approach, the endogenous or non-endogenous receptor may be in reference to an in vitro selection system. As a further example and without limitation, when the genome of a mammal has been engineered to include a non-endogenous constitutively active receptor, selection of a candidate compound by means of an in vivo system is feasible. FUSION PROTEIN OF THE COUPLED RECEIVER PROTEIN G and FUSION PROTEIN GPCR, in the context of the invention described herein, each means a non-endogenous protein comprising a constitutively activated, endogenous, orphan GPCR fused to at least one G protein, more preferably, the alpha subunit ( a) of such G protein (this being the subunit that binds GTP), with the G protein being preferably the same time as the G protein which is naturally coupled with endogenous orphan GPCR. For example, and without limitation, in an endogenous state, the "Gsa" G protein is the predominant G protein that is coupled with GPR6 so that a GPCR Fusion Protein based on GPR6 would be a non-endogenous protein comprising GPR6 fused to Gsa. The G protein can be fused directly to the c-terminus of the constitutively active orphan endogenous GPCR or there can be spacers between the two. INHIBITING OR INHIBITING, in relation to the term "response" must mean that a response is reduced or prevented in the presence of a compound as opposed to in the absence of the compound. INVERSE AGONISTS must mean portions that bind the endogenous form of the receptor, and that inhibit the intracellular baseline response initiated by the active endogenous form of the receptor below the normal base level of activity that is observed in the absence of the endogenous ligand, agonists or partial agonists, or reduce GTP that binds to the membranes. Preferably, the intracellular baseline response is reduced in the presence of the inverse agonist by at least 30%, more preferably at least 50% and more preferably at least 75%, compared to the baseline response in the absence of the inverse agonist . Biologically, the "inverse agonist of GPR6" must mean portions that can be assessed in vivo by different factors just at the determination that the portion has interacted with GPR6, for example, when the portion interacts with a mammalian GPR6 in vivo, there is a reduction observed in mammalian body weight by at least about 5% within 24 to 48 hours of contact of GPR6 and the inverse agonist of GPR6. BINDER must mean a molecule that occurs naturally, endogenously specific to a receptor that occurs naturally, endogenously.

PHARMACEUTICAL COMPOSITION should mean a composition comprising an Active Ingredient and at least one ingredient that is not an Active Ingredient (eg, and without limitation, a filler, dye, or a mechanism for slow release), whereby the composition is willing to research for an effective consequence, specified in a mammal (for example, and without limitation, a human). Those of ordinary skill in the art will understand and appreciate the appropriate techniques to determine whether an active ingredient has a desired effective consequence based on the needs of the user. artist. SMALL MOLECULE, in the context of the invention described herein, is a non-protein based portion; for example, and without limitation, ARE 1 1 2 is a small molecule within the context of this invention, whereas the binder for a receptor is not a small molecule.

DETAILED DESCRIPTION A. Introduction The traditional study of receptors has always proceeded from a previous assumption (historically based) that the endogenous ligand must first be identified before the discovery could proceed to find antagonists and other molecules that could affect the receptor. Even in cases where an antagonist must have met first, the investigation immediately extends to look for the endogenous ligand. This way of thinking has persisted in the research of the receiver even after the discovery of constitutively active receptors. What has not been recognized is that it is the active state of the receptor that is most useful for discovering agonists, partial agonists and inverse receptor agonists. For those diseases that result in too active a receptor, what is desired in a therapeutic drug is a compound that acts to decrease the active state of a receptor, not necessarily a drug that is an antagonist to the endogenous ligand. This is because a compound (eg, therapeutic) that reduces the activity of the active receptor state does not need to bind in the same site as the endogenous ligand. Thus, as taught by a method of this invention, any search for the therapeutic compounds should begin by selecting the compounds against the active state independent of the binder. The investigation, then, is for an inverse agonist to the active state receiver. The selection of candidate compounds against orphan receptors, for example, including but not limited to, GPR6 and GPR6 Fusion Protein, allows the direct identification of candidate compounds that act on this orphan cell surface receptor, without requiring any prior recognition or use of the receptor's endogenous ligand. By determining the areas within the body where such receptors are expressed and / or overexpressed, it is possible to determine related disease / disorder states that are associated with the expression and / or overexpression of these receptors; such an approach is described in the patent document.

B. Identification and / or Disease / Disorder Selection As set forth in more detail below, the agonists and agonists preferably inverse to GPR6 can be identified by the methodologies of this invention. Such agonists and inverse agonists are ideal candidates as lead compounds in drug discovery programs to treat diseases related to this receptor. However, an antagonist to such a receptor (even if the binder is known) may be ineffective since the receptor is still activated. in the absence of binding ligand-receptor. Due to the ability to directly identify agonists and inverse agonists to these receptors, thus allowing the development of pharmaceutical compositions, research is possible for diseases and disorders associated with these receptors. For example, GPR6 is expressed in the following areas of the brain: lateral hypothalamus, hippocampus, nucleus, cerebral cortex and caudato. Given the elevated levels of expression in brain areas associated with feeding behavior and metabolism, GPR6 is probably related to a variety of disorders and diseases related to abnormal food intake and / or metabolism, for example, clinical obesity. C. Selection of Candidate Compounds 1. Generic GPCR selection analysis techniques When a G protein receptor becomes constitutively active, it binds to a G protein (eg, Gq, Gs, Gi, Go) and stimulates the binding of GTP to protein G. The protein G then acts as a GTPase and slowly hydrolyses the GTP in GDP, whereby the receptor, under normal conditions, becomes deactivated. However, constitutively active receptors continue to exchange GDP in GTP. A non-hydrolysable analogue of GTP, [35S] GTP? S, can be used to monitor the increased binding to membranes expressing constitutively activated receptors. It is reported that [35S] GTP? S can be used to monitor the G protein that is coupled to the membranes in the absence and presence of binder. An example of this monitoring, among other well-known examples available for those in the material, was reported by Traynor and Nahorski in 1959. Generally, this preferred use of this analysis system is for the initial selection of candidate compounds because the system is generally applicable to all coupled G protein receptors without considering the particular G protein that interacts with the intracellular domain of the receptor. 2. Specific GPCR selection analysis techniques Once the candidate compounds are identified using the "Generic" G protein coupled receptor analysis (ie, an analysis to select compounds that are agonists, partial agonists, or inverse agonists) , additional selection is preferred to confirm that the compounds have interacted at the receptor site. For example, a compound identified by the "generic" assay may not bind to the receptor, but may instead merely "uncouple" the G protein from the intracellular domain. Thus, in selecting those candidate compounds, which have been identified using a "generic" analysis in a competitive binding analysis of antagonist and / or agonist, additional refinement is provided in the selection process. In the case of GPR6 it has been determined that this receptor couples the G Gs protein. Gs stimulates enzyme adenylyl cyclase (Gi, or on the other side, inhibits this enzyme). The adenylyl cyclase catalyzes the conversion of ATP into cAMP; thus, assays that detect a cAMP can be used, for example and without limitation, cAMP analysis on a cell basis, to determine whether a candidate compound is an inverse agonist to the receptor (i.e., such a compound that contacts the receptor would reduce cAMP levels relative to the non-contacted receiver). As a result, the "cyclase-based assay" can be used to select additionally those compounds selected from a competitive agonist and / or antagonist binding assay. 3. GPCR Fusion Protein The use of a constitutively activated, endogenous orphan GPCRs, such as GRP6, for use in the selection of candidate compounds for the direct identification of inverse agonists, agonists and partial agonists, provides a unique change in that, By definition, the endogenous receptor is active even in the absence of an endogenous ligand attached thereto. In this way, in order to differentiate between, for example, the endogenous receptor in the presence of a candidate compound and the endogenous receptor in the absence of that compound, for a purpose of such differentiation to allow an understanding as to whether such a compound can be an inverse agonist, agonist, partial agonist or have no affect on such a receptor, it is preferred that an approach is used that can increase such differentiation. A preferred approach is the use of a GPCR Fusion Protein. Generally, once it is determined that an endogenous orphan GPCR is constitutively activated, using the analysis techniques set forth above (as well as others), it is possible to determine the predominant G protein that is coupled to the endogenous GPCR. The coupling of the G protein to the GPCR provides a signaling path that can be assessed. Because selection is more preferred to take place by the use of a mammalian expression system, such a system will be expected to have endogenous G protein therein. Thus, by definition, in such a system, the constitutively active, endogenous orphan GPCR will be continuously signaled. In this aspect, it is preferred that this signal be increased so that in the presence of, for example, an inverse agonist to the receptor, it is more likely that one will be able to differentiate more easily, particularly in the context of selection, between the receiver when contacting the inverse agonist. The GPCR Fusion Protein is proposed to increase the efficiency of the G protein that is coupled with endogenous GPCR. The GPCR Fusion Protein appears to be important to be selected with a constitutively active, endogenous GPCR because such an approach increases the signal that is preferably used in such selection techniques. It is important to facilitate a significant "signal to noise" ratio. A significant proportion is preferred for the selection of candidate compounds as described herein.

The construction of a construct useful for the expression of the GPCR Fusion Protein is within the field of those who have ordinary experience in the field. Commercially available expression vectors and systems offer a variety of approaches that can be tailored to the particular needs of an investigator. The criterion of importance of such a GPCR Fusion Protein construct is that both the endogenous GPCR sequence and the G protein sequence are in structure (preferably, the sequence for the endogenous GPCR is upstream of the G protein sequence). ) and that the "stop" codon of the GPCR must be deleted or replaced in such a way that after the expression of the GPCR, the G protein can also be expressed. The GPCR can be directly linked to the G protein, or there can be spacer residues between the two (preferably, no more than about 12, although this number can be easily guessed by someone of ordinary skill in the art). Both approaches have been evaluated, and in terms of measurement of GPCR activity, the results are substantially the same: however, there is a preference (based on convenience) for using a spacer in that some reaction sites that are not used , after the expression, a spacer will become effectively. More preferably, the G protein that is coupled to the endogenous GPCR will have been identified prior to the creation of the GPCR Fusion Protein construct. Because there are few G proteins that have been identified, it is preferred that a construct comprising the G protein sequence (ie, a universal G protein construct) be available for the insertion of an endogenous GPCR sequence into the same; this is provided for efficacy in the context of large-scale selection of a variety of different endogenous GPCRs having different sequences. D. Pharmaceutical Composition Candidate compounds for further development as active ingredients can be formulated into pharmaceutical compositions using techniques well known to those skilled in the art. Suitable pharmaceutically acceptable carriers are available to those skilled in the art, for example, see Remington's Pharmaceutical Sciences, 6th Edition, 1 980, Mack Publishing, Co., (Oslo et al., Eds.). EXAMPLES The following examples are presented for elucidation purposes, and without limitation, of the present invention. The particular order for the selection techniques stated below is classified for presentation efficiency. Although the specific amino acid and nucleic acid sequences are described herein, those of ordinary skill in the art are credited with the ability to make modifications to these sequences while achieving the same or substantially similar results reported below. EXAMPLE 1 EXPRESSION OF THE RECEIVER 1. cDNA and Vectors The expression vector comprising GPR6 cDNA was generously provided by Brian O'Dowd (University of Toronto). The vector used for GPR6 was pRcCMV (the coding region for GPR6 was subcloned into the pCMV vector in a Hindlll-Xbal site). See, I KNOW THAT. ID. NO: 1, for the nucleic acid sequence and SEQ. ID. NO: 2 for the amino acid sequence of GPR6. 2. Transfection Procedure On day one, 293 1 X107 cells per 150 mm plate were placed outside the plate. On day two, two reaction tubes were prepared (the proportions to be followed for each tube are per plate): tube A was prepared by mixing 20 μg of DNA (eg, pCMV vector; pPRV vector GPR6 cDNA; pCMV vector: Fusion protein) in 1.2 ml of DMEM-free serum (Irvine Scintific, Irvine, CA); Tube A was prepared by mixing 120 μl of lipofectamine (Gibco BRL) in 1.2 ml of DMEM-free serum. Tubes A and B were then mixed by inversions (several times), followed by incubation at room temperature for 30-45 min. The mixture is referred to as the "transfection mixture". The 293 cells placed on the plate were rinsed with 1 X PBS, followed by the addition of 10 ml of DMEM-free serum. 2.4 ml of the transfection mixture were then added to the cells, followed by incubation for 4 hrs at 37 ° C / 5% CO2. After 72 hrs of incubation, the cells were harvested and used for analysis. EXAMPLE 2 PREPARATION OF THE GPCR FUSION PROTEIN The design of a Fusion Protein construct of GPC6 was carried out as follows: both 5 'and 3' ends of the Gsa rat G protein (long form: Itoh, H. , et al., 83 PNAS 3776 (1986)) were designed to include a Hindlll sequence (5'-AAGCTT-3 ') therein. After confirmation of the correct sequence (including Hindlll flanking sequences), the entire sequence was moved to pcDNA3. 1 (-) (Invitrogen, Cat. No. V795-20) by subcloning using the Hindlll restriction site of that vector. The correct orientation for the Gsa sequence was determined after subcloning into pcDNA3. 1 (-). The pcDNA3. 1 (-) modified containing the rat Gsa gene in the Hindlll sequence was then verified; this vector is now available as a "universal" Gsa protein vector). The vector pcDNA3.1 (-) contains a variety of well-known restriction sites upstream of the HindIII site, thus beneficially providing the ability to insert, upstream of the Gs protein, the coding sequence of a constitutively active GPCR, endogenous. This same approach can be used to create other "universal" G protein vectors, and, of course, other available patented or commercially available vectors known to the technician can be used, the important criterion being that the sequence for the GPCR is upstream and structured with that of the G protein. The construction of the GPR6-Gsa Fusion Protein was made as follows: the starting charges used were as follows: 5'-gatcTCTAGAATGCAGGGTGCAAATCCGGCC-3 '(SEQ ID NO.3, sensitive) 5 -ctagGGTACCCGGACCTCGCTGGGAGACCTGGAAC-3 '(SEQ ID NO.4, antisensitive). The start loads, sensitive and antisensitive, also contained restriction sites for Xbal and Kpnl, respectively. These restriction sites are available upstream of the Hindlll site in the pcDNA3 vector. 1 (-). PCR was then used to secure the respective receptor sequences for fusion within the universal Gsa vector described above, using the following procedure for each: 100 ng of cDNA for GPR6 were added to separate tubes containing 2 ul of each charge. start (sensitive and antisensitive), 3 uL of 10 mM dNTPs, 1 0 uL of 10XTaqPlus ™ regulator Accuracy, 1 uL of TaqPlus ™ Precision polymerase (Stratagene: # 60021 1) and 80 uL of water. Reaction temperatures and cycle times were as follows: the initial denaturation step was done at 96 ° C for seven minutes, and a cycle of 96 ° C for 30 seconds, 55 ° C for 30 seconds, and 72 ° C for two minutes they were repeated 30 times. A final extension time of ten minutes at 72 ° C was made for GPR6. The PCR products for GPR6 were passed on 1% agarose gel and then purified (data not shown). The purified product was digested with Xbal and Kpnl (New England Biolabs) and the desired inserts were isolated, purified and ligated into the universal vector of Gs at the respective restriction site. Positive clones were isolated after transformation and determined by restriction enzyme digestion; Expression using 293 cells was carried out following the procedure set forth below. The positive clone for GPR6: Gsa Fusion Protein was sequenced and made available for the direct identification of candidate compounds. See, SEQ.ID.NO:5 for the nucleic acid sequence and SEQ. ID.NO:6 for deduced amino acid sequence of GPR6: Gsa Fusion Protein. EXAMPLE 3A ASSESSMENT OF CONSTITUTIVE ACTIVITY USING ADENILIL CYLASE ANALYSIS A Flash Platy ™ Adenyl Cyclase kit (New Egland Nuclear; Cat. No. SMP004A) designed for cell-based analysis can be modified for use with plasma membranes. raw. The Flash Pita cavities contain a scintillating coating that also contains a specific antibody that recognizes cAMP. The cAMP generated in the cavities can be quantified by a direct competition for the binding of the radioactive cAMP indicator to the cAMP antibody. The following serves as a method for measuring changes in cAMP levels in whole cells expressing receptors, for example, GPR6 or GPR6: Gsa Fusion Protein. The transfected cells were harvested approximately twenty-four hours after the transient transfection. The media was sucked and discarded carefully. 10 ml of PBS was added gently to each cell dish followed by careful aspiration. 1 ml of Sigma cell dissociation regulator and 3 ml of PBS were added to each plate. The cells were pipetted from the plate and the cell suspension was collected in a 50 ml conical centrifuge tube. The cells were then centrifuged at room temperature at 1, 100 rpm for 5 min. The cell pellet was carefully re-suspended in an appropriate volume of PBS (approximately 3ml / plate). The cells were then counted using a hemocytometer and additional PBS was added to give the appropriate number of cells (with a final concentration of approximately 50x1 04 / well). The cAMP standards and the Detection Regulator (comprising 1 μCi of indicator [125 μl cAMP (50 μl) for 1 μl of Detection Regulator) were prepared and maintained according to the manufacturer's instructions. (preferably fresh, prepared) to select and containing 50 ul of Stimulation Regulator, 3 ul of test compound (12 uM of final analysis concentration) and 50 ul of cells, the Stimulation Regulator can be stored on ice until it is use Analysis can be initiated by addition of 50 ul of cAMP standards to appropriate cavities followed by the addition of 50 ul of PBSA to the cavities H-1 1 and H 1 2. 50 ul of Stimulation Regulation were added to all the cavities. DMSO (or selected candidate compounds) were added to appropriate cavities using a needle tool capable of distributing 3 ul of compound solution, with a final analysis concentration of 1 2 uM of test compound and 1 00 ul of total assay volume. The cells were then added to the wells and incubated for 60 min at room temperature. 1 00 ul Detection Regulator containing cAMP indicator was then added to all the cavities. The plates were then incubated an additional 2 hours after counting in a Wallac MicroBetal scintillation counter. The cAMP / cavity values were then extrapolated from a standard cAMP curve that is contained within each assay plate.

GPR6 and GPR6: Gsa Fusion Protein were analyzed as above and verified to be constitutively active, whereby GPR6: Fusion Protein evidenced approximately a 4-fold increase in cAMP over GPR6 (see, Figure 1). In the context of selection of candidate compounds, when the objective is to identify inverse agonists, agonists or partial agonists, it is preferred that the signal to noise ratio is maximized (especially in the case of selecting inverse agonists). In this way, although it is feasible to use GPR6 by itself, given the substantial increase in this proportion, the use of GPR6: Gsa Fusion Protein is particularly preferred (although someone with ordinary experience in the field will be credited with selecting an approach that is based on the particular needs of the technician). It is further noted that there does not appear to be an "upper limit" or "roof" for the signal so that despite the increase in the signal evidenced in Figure 1, these constructs can also be used for selection to determine GPR6 agonists (ie , an agonist will also increase the signal). EXAMPLE 3B CONSTITUTIONAL ACTIVITY ASSESSMENT USING GTP MEMBRANE BINDING PROXIMITY PROXIMITY ANALYSIS The use of [35S] GTP? S binding to measure constitutive activation may be advantageous in that: (a) the binding of [35S] GTP? S is generically applicable to all coupled G protein receptors; and (b) the binding of [35S] GTP? S is close to the membrane surface, thus making it less likely to pick up molecules that affect the intracellular cascade. Preferably, GPCR: Fusion Protein is used. The analysis utilizes the ability of coupled G protein receptors to stimulate the binding of [35S] GTP? S to membranes that express the relevant receptors. Therefore, the analysis can be used to directly select compounds in the described GPR6 receiver. A scintillation proximity analysis was used to monitor the binding of [35 S] GTPγS to membranes expressing, for example, GPR6: Human, endogenous Gs Fusion Protein (expressed in 293 cells). In short, a preferred method for analysis is such that the assay was incubated in 20 mM HEPES, pH 7.4, binding buffer (1 00 mM NaCl and 10 mM MgCl 2), with 0.6 nM of [35 S] GTP? S and 12.5 μg of membrane protein and 0.1 μM of GDP for 60 minutes. The assay plates were then centrifuged at 4000 rpm for 15 minutes at room temperature and then subsequently aspirated and counted in a scintillation counter. Using this analysis, the enhanced binding of [35S] GTP? S to membranes prepared from 293 cells expressing the control vector alone or the GPR6: Human Gsa Fusion Protein receptor was observed comparatively. The total protein concentration used in the analysis affects the total amount of [35 S] GTP? S binding for each receptor. The differential c.p.m. between transfected pCMV and the GPR6 receptor: constitutively active Gsa Fusion Protein (at 12.5 ug / ml) increased from about 6000 c. p. m to approximately 1 1, 600 c. p. m of protein concentration. The results are presented in Figure 2 and the evidence that the GPR6 receptor (GPR6: Gsa Fusion Protein) has increased activity compared to the control; this increasing activity is not the result of autocrine stimulation in that the data were obtained from membrane preparations, as opposed to all complete cell preparations. EXAMPLE 4A DIRECT IDENTIFICATION OF INVERSE AGONISTS AND AGONISTS USING ANALYSIS OF [35S] GTP? S Although constitutively active, endogenous GPR6 has been used for the direct identification of candidate compounds as, for example, inverse agonists, for reasons they do not fully understand, The intra-analysis variation can be exacerbated. Preferably, then, a GPCR Fusion Protein, as described above, is used. When such a protein is used, the intra-analysis variation appears to be substantially stabilized, whereby an effective signal-to-noise ratio is obtained. This has the beneficial effect of allowing a more robust identification of candidate compounds. The following procedure is preferred: 1. Membrane Preparation Membranes expressing GPCR6: Gase Fusion Protein (see, Example 2) and to be used in the direct identification of candidate compounds as inverse agonists, agonists or partial agonists were prepared as follows: (a) Membrane Scraping Regulator Materials are comprised of 20 mM HEPES and 10 mM EDTA , pH 7.4; Membrane Rinsing Regulator is comprised of 20 mM of HEPES and 0.1 mM of EDTA, pH 7.4; Union regulator is comprised of 20 mM HEPES, 1 00 mM NaCl, and 10 mM MgCl2, pH 7.4. (b) Procedure All the materials were kept in the smell during the procedure. First, the medium was aspirated from a confluent monolayer of cells, followed by rinsing with 10 ml of cold PBS, followed by aspiration. Then, 5 ml of membrane scraping regulator was added to scraping cells; this was followed by the transfer of the cell extract in 50 ml centrifuge tubes (centrifuged at 20,000 rpm for 1 7 minutes at 4 ° C). Therefore, the supernatant was aspirated and the pellet resuspended in 30 ml of Membrane Rinsing Regulator followed by centrifuge at 20,000 rpm for 17 minutes at 4 ° C. The supernatant was then aspirated and the pellet resuspended in Union Regulator. This was then homogenized using a Brinkam polytron ™ homogenizer (abrupt ionizations of 1 5-20 seconds until all the material was in suspension). This is referred to herein as "Membrane Protein". 2. Bradford Protein Analysis After homogenization, the protein concentration of the membranes was determined using Bradford Protein Analysis (the protein can be diluted to approximately 1.5 mg / ml, aliquoted and frozen (-80 ° C) to After use, when frozen, the procedure to be used is as follows: on the day of analysis, the frozen membrane protein thaws at room temperature, followed by vortex and then homogenized with a polyuitron at approximately 12 x 1,000 rpm for approximately 5-1 0 seconds, it is observed that for multiple preparations, the homogenizer must be completely cleaned between the homogenization of different preparations). The membrane protein concentrations are revalued and normalized to CMV where the optimum protein concentration is between 0.25 ug / ul and 0.30 ug / ul. (a) Union Regulatory Materials (as above); Bradford Tint Reagent; Bradford Protein Standard, were used following the manufacturer's instructions (Biorad, Cat. No. 500-0006). (b) Procedure Duplicate tubes were prepared, one including the membrane, and the other as a control "space". Each one contained 800ul of Union Regulator. Then, 1 0 ul of Bradford Protein Standard (1 mg / ml) was added to each tube, and 10 ul of membrane protein was then added to only one tube (not the space). Then, 200 ul of Bradford Dye Reagent was added to each tube, followed by each vortex. After five (5) minutes, the tubes were re-vortexed and the material in them was transferred to cuvettes. The cuvettes were then read using a CECIL 3041 spectrophotometer, at wavelength 595. 3. Direct Identification Analysis (a) Materials The GDP regulator consisted of 37.5 ml of Union Regulator and 2 mg of GDP (Sigma, no. cat. G-7127), followed by a series of dilutions in the Union Regulator to obtain 0.2 uM of GDP (final concentration of GDP in each cavity was 0.1 uM of GDP); each cavity comprising a candidate compound, had a final volume of 200 ul consisting of 1000 ul of GDP Regulator (final concentration, 0. 1 uM of GDP), 50 ul of Membrane Protein (12.5 ug) in Union Regulator , and 50 ul of [35 S] GTP? S (0.6 nM) in Union Regulator (2.5 ul of [35 S] GTP? S per 10 ml of Union Regulator). (b) Procedure Candidate compounds (Tripos, Inc., St. Louis, MO) were received in 96-well plates (these can be frozen at -80 ° C). Membrane Protein (or membranes with expression vectors that exclude GPR6: Gsa Fusion Protein, as control), were briefly homogenized until the suspension. The protein (and control) concentration was then diluted to 0.25 mg / ml in Union Regulator (final analysis concentration, 12.5 ug / well). Then, 100 ul of GDP regulator was added to each cavity of a Wallac Scintistrip ™ (Wallac). A 5 ul needle tool was then used to transfer 5 ul of a candidate compound in such a cavity (ie, 5 ul in the total assay volume of 200 ul is a 1: 40 ratio so that the final selection concentration of the candidate compound is 1 0 uM). Again, to avoid contamination, after each transfer step the needle tool was rinsed in three containers comprising water (1 X), ethanol (1 X) and water (2X), the excess liquid should be stirred from the tool after each rinse and dry with paper towels or kimwipes ™. Then, 50 ul of Membrane Protein was added to each well (a control well comprising membranes without the GPCR Fusion Protein is also used), and pre-incubated for 5-1 0 minutes at room temperature (the plates were covered with metallized paper since the candidate compounds obtained from Tripos are sensitive to light). Then, 50 ul of [35S] GTP? S (0.6 nM) in Binding Regulator was added to each well, after incubation in a shaker for 560 minutes at room temperature (again, in this example, the plates were covered with metallic paper). The analysis was then aspirated with an 8 channel manifold and sealed with plastic plate covers. The plates were then read on a Wallac 1450 using the "Prot # 37" facility (as per manufacturer's instructions). EXAMPLE 4B DIRECT IDENTIFICATION OF "GUIDES" We believe it is important to note that the following results have been obtained using an orphan receiver; as the data carriers, it is possible, using the techniques described herein, to directly identify the candidate compounds that modulate the orphan receptor as inverse agonists, agonists and partial agonists, directly from a primary selection; however, the methods described herein are sufficiently sensitive to allow direct identification of both inverse agonist and agonist modulators in the same assay plate.

The initial or "primary" selection designed to directly identify, for example, human GPR6 receptor inverse agonists, consisted of the membrane-based GTP? S-binding assay of Example 4A using membranes prepared from 293 stable cells. Candidate compounds directly identified as increases mediated by the inhibition receptor on GTPγS as set forth below, were considered active "guides". The primary analysis guides were then rejected in the same analysis to reconfirm their inverse agonist activity. If the impacts in the primary analysis were reconfirmed as active (50% or greater inhibition), and were therefore directly identified as, for example, an inverse agonist, the additional candidate compounds were synthesized based on the structures of the reconfirmed impacts. (prepared to, for example, improvement in the characteristics of the compounds) whereby the targeted library compounds (Arena Pharmaceuticals, Inc., San Diego CA) were then evaluated. The last stage in the secondary analysis evaluation was to determine whether the test compounds were able to inhibit the accumulation of cAMP (ie, analysis based on adenylate cyclase, described below in Example 4C). This final analysis confirms that the directly identified compounds retained inverse agonist properties. A result of the representative selection analysis plate (96 cavity format) is presented in Figure 3. Each bar represents the results of a different compound in each cavity, plus GPR6: Fusion Protein Gs. The representative results presented in Figure 3 also provide standard deviations based on the average results of each plate ("m) and the average plus two standard deviations (" m + 2sd ") and the average minus two standard deviations (" m- 2sd ") Our arbitrary preference for the selection of inverse agonists as" guides "of the primary selection includes the selection of candidate compounds that reduce the percent response by at least the average plate response, minus two standard deviations. to this selection process, the candidate compounds in the following cavities were directly identified as putative inverse agonists to the GPR6 receptor: A7; B2; F6; G6 and H6.Additional evaluation (using a non-GPR6 receptor) of designated compounds in the cavities A7, B2, F6 and G6 indicated that these compounds were not specific for the GPR6 receptor: Gs Fusion Protein and thus can instead act to decouple the G protein from the GPR6 receptor (data not shown). In this manner, the candidate compound of the H6 cavity, designated "ARE 1 12" was selected for further evaluation. It is preferred that by following such direct identification, the IC50 (inverse agonist) or EC50 (agonist) values are determined; those who have ordinary experience in the matter are credited with using the analysis procedures of choice of IC50 or EC50. Figure 4 provides a representative IC 50 curve for compound ARE 1 1 2 using the analysis procedure of Example 4A. EXAMPLE 4C CYCLIC CONFIRMATION ANALYSIS Using an independent analysis approach to provide confirmation of a directly identified candidate compound as set forth above, it is preferred that a confirmation analysis be used then. In this case, the preferred confirmation analysis is membrane-based cyclic AMP analysis (cAMP). A modified Adenilil Flash Piet ™ Cyclase kit (New England Nuclear; Cat. No. SMP004A) was used for the confirmation of candidate compounds directly identified as inverse agonists and agonists to constitutively activated, orphan, GPRCs constituted endogenously according to the following procedure . Stable transfected cells were harvested approximately three days after transfection. The membranes were prepared by homogenization of suspended cells in regulator containing 20 mM HEPES, pH 7.4 and 1.0mM MgCl2. Homogenization was carried out on ice using a Polytron ™ Brinkman for approximately 10 seconds. The resulting homogenate was centrifuged at 20,000 rpm for 20 minutes at 4 ° C. The resulting pellet was then resuspended in buffer containing 20 mM HEPES, pH 7.4 and 0. 1 mM EDTA, homogenized for 10 seconds, followed by centrifugation at 20,000 rpm for 20 minutes at 4 ° C. The resulting tablet can be stored at -80 ° C until used. On the day of direct identification screening, the membrane pellet was thawed slowly at room temperature, resuspended in a buffer containing 20 mM HES EPES, pH 7.4, 1 00 mM NaCl and 1.0 mM MgCl2, to produce a concentration of final protein of 0.60 mg / ml (the resuspended membranes were placed on ice until used). The cAMP and Detection Regulator standards (comprising 2 μCi of [125 μl cAMP (50 μl) for 1 μl of Detection Regulator) were prepared and maintained according to the manufacturer's instructions. selection and contained 20 mM HEPES, pH 7.4, 100 mM NaCl, 1.0 mM MgCl2, 20 mM phospocreatine (Sigma), 0.1 unit / ml creatine phosphokinase (Sigma), 50 μM GTP (Sigma) , 0.2 mM of ATP (Sigma) and 0.6 mM of isobutyl methyl xanthine (IBMX); The Analysis Regulator can be stored on ice until it is used. The candidate compounds identified above (if frozen, thaw at room temperature) were added to the wells of the dish (3 μl / well, 1 2 μM final assay concentration), together with 50 μl of Membrane Protein (30 μg). / cavity) and 50 μl of Analysis Regulator. This mixture was then incubated for 30 minutes at room temperature, gentle agitation. After incubation, 1 00 μl of Detection Regulator were added to each well, after incubation for 2-20 hours.

Plates were subsequently aspirated and then counted in a Wallac Microbeta ™ plate reader using "Prot. # 31" (as per the manufacturer's instructions). The following Table A lists the IC50 values determined using the previous cAMP analysis.

Table A Preferably, for the determination of IC5o, the dose response range at the maximum is between 80 and 120 percent control ("% control"), and at least between 20 and -20 percent control, although such parameters may be a matter of choice for the technician, depending on the particular needs of the technician. EXAMPLE 5 SELECTION OF THE DIRECTED LIBRARY Based on the following results, in analysis of the structure activity of compound ARE1 12 suggests that a series of derivatives of ARE1 12, N- (5,6-dihydro-3H-imidazo [2, 1-c] -1, 2,3-dithiazol-3-ylidene), as well as derivatives of ARE 1 1 1 N- (2-thioxo-imidazolidine-1 -carbotioyl) would exhibit selectivity and similar inverse agonist activity of GPR6. .

A directed library series of N- (5,6-dihydro-3H-imidazo [2, 1-c] -1, 2,3-dithiazol-3-ylidene) and N- (2-thioxo-imidazolidine) derivatives -1-carbothioyl) were synthesized (see Examples 8 and 9, infra). The IC 50 values were determined using the analyzes indicated below, by taking the average values of the analysis number (placed in brackets), +/- the standard deviation. These were assessed too much using the above procedures, and the results are summarized below in Table B: TABLE B EXAMPLE 6 LIVE IN ANALYSIS 1. Food / Water intake and Body Weight in Private Food Animals for 24 hours. The ARE 1 1 2 profile of in vitro functional analyzes suggested that this compound exhibits selective GPR6 inverse agonist properties. An in vivo assessment of GPR6 inverse agonist was carried out by detecting the effects of ARE 1 12 on food intake after deprivation in rats. Food deprivation was used to induce higher than normal eating behavior (for example, animals treated with the vehicle / control were hyperphagic). The animals (male Sprague-Dawley rats were used for the following experiments) were deprived of food for 24 hr, and then were injected mperperitoneally (PI) with 0, 6.75, 1 3.5, 27 and 54 mg / kg of compound AR E 1 1 2. After 30 min, rats were fed standard rat feed pellets and thereafter observed for a period of 6.5 hours after injection. Evidence data that IP treated animals with compound ARE 1 12 show water intake and reduced food intake, and body weight gain. In Figure 5A, at 1.5 hours after injection, animals treated with the vehicle consumed approximately 6 grams of food, while those treated with ARE 1 1 2 (54 mg / kg) consumed 3g of food. As time passes, the data indicate that those treated with the vehicle eat substantially more food (up to 14 kg in 6.5 hours after injection), while those treated with ARE 1 12, particularly animals treated with 54 mg / ñg of ARE 1 12, they consumed 4 g (see, Figure 5A). Four- and five-fold reductions in water intake at doses of 27 and 54 mg / kg, respectively, were also evidenced by the data, which appear to equal the reduced amount of food eaten (See, Figure 5B). The rats treated with the vehicle showed a body weight gain of 20 g, while the rats treated with ARE1 12 showed the following: 1 3.5 mg / kg of treatment - 1 1 g of weight gain; 27 and 54 mg / kg of treatment, without weight gain (see, Figure 5C). 2. Food intake / Basal water and body weight in animals not deprived of food The animals were also observed during their most active period (dark cycle) and both the basal intake of food and water were measured. In this test, the animals were not deprived of food but instead they were observed for their normal activity. The animals were administered ARE 12 in 0, 6.75, 1 3.5, 27 and 54 mg / kg, IP 30 min before starting the dark cycle (ie, 6:30 pm) and then exposed to food pellets. for standard rats (ie, 30 min after administration of the compound) and were observed for a period of 1 5.5 hr after administration. The data, presented in Figure 6A, show that the animals administered with ARE 1 1 2 do not eat as much as the animals administered with the vehicle. For example, the animals treated with the vehicle consumed 9 g of food for a period of 4 hours, while the animals treated with doses of 13.5 mg / kg and 54 mg / kg consumed less than half of this amount during this same period (4 and 2 g of food, respectively). Similar to food-deprived rats, non-private rats also showed a reduction in water intake and body weight gain (see Figures 6B and 6C). The long-term effects (60 days) of ARE 1 12 were also examined. The animals (treatment, n = 4; control, n = 5) were treated once daily intraperitoneally with ARE1 12 for 22 days and assessed for a period of 60 days. On days 1 to 3, the animals treated with the dose of 3.5 mg / kg initially lost body weight and between day 4 on day 31, the animals gradually gained weight, although they still weigh less than the animals treated with the vehicle. After day 31, and day 60, the data support the position that there is a significant difference in body weight between the treated animals and the vehicle animals. The data support the conclusion that repeated daily administration of ARE 1 12 (at 1 3.5 mg / kg) induces a long-term reduction in body weight in rats not deprived of food. See, Figure 1 1. 3. Intracerebroventricular Administration (ICV) of ARE1 12 in Private Food Animals a. Surgery The animals were prepared with ICV cannula pointed above the lateral ventricle. For this surgery, the animals were placed under general anesthesia using continuous isofliran inhalation and secured in a Kopf stereotaxic instrument. The surgery was carried out in a dedicated surgery room, using sterile instruments, surgical gloves and aseptic procedures to prevent clinical infections. The surgical site was shaved and disinfected with betadine and alcohol solution. The animals were continuously observed for the level of anesthesia when testing the animals' responses to tail or leg perforation. A cannula made of 23 gauge stainless steel tube (7 mm long) was lowered to a point 1 mm above the ventricle, using the coordinates: A / P - 0.6 mm bregma, M / L +/- 20 mm bregma , D / V 3.2 mm below the surface of the skull. The guide was extended to the skull with three stainless steel screws and dental cement.

The coordinates were based on the stereotactic atlas such as Stellataxic atlas of Paxinos and Watson (Paxinos, G and Watson, C, The Rat Brain, New York, Academic Press, 1 982). After implantation of the cannula, a 30-gauge stainless steel stylet was inserted into the cannula. At the conclusion of the surgery, a heat source (heat lamp directed towards one half of the recovery box) was used to maintain body temperature while the animals recovered from anesthesia. The animals were left at least one week in recovery after surgery before the ICV injection of the compound was carried out. b. Administration of ARE1 12 The animals were deprived of food for 24 hours before the administration of the compound. For the injection of ICV, the model stylet was removed from the implanted cannula, and a 30-gauge stainless steel injection cannula containing the suspension of ARE 1 12 in a 45% solution of cyclodextrin was inserted at a depth of 1.5 mm beyond the ventral tip of the implanted cannula. The other (non-inserted) end of the injection cannula is attached to 60 cm of PE 10 tube containing the suspension of the compound, which is attached to the free end of the tube to a Hamilto 25 μl syringe. Ten microwells of ARE1 12 suspension (containing, 0, 25, 50 and 1 00 nmol) were then supplied through uniform and gentle mechanical pressure to the pressure contact of the Hamilton syringe. The injection volume was verified by markings on the PE 1 0 tube previously calibrated with a Hamilton syringe of 10 μl. At the conclusion of the injection, any fluid observed from the dorsal tip of the cannula implanted in the extraction of the injection cannula was observed, and the model stylet was inserted into the implanted cannula. Evidence data that after two hours after the administration of ARE 1 1 2 in all doses, the animals consumed substantially less food (approximately 6 times less food was consumed). After three hours, the vehicle rat consumed approximately 2.5 grams of feed, while the rats treated with ARE 1 12 consumed approximately 1.0 grams or less. See, Figure 7A. The treated animals (at 25 and 50 nmol) drank a comparable amount of water as the vehicle, i.e. approximately 1.7 grams. At higher doses (eg, 1 00 nmol), approximately less than half of that amount was consumed. See, Figure 7C. The data show, consistent with the data developed using IP administration, that in a dose of 100 nmol of ARE 1 1 2, the animal treated with ICV gained substantial weight (for example, 5 grams) when evaluated against the vehicle, which gained approximately 12 grams. See, Figure 7C. 4. Effect of ARE1 12 on the Motor Function The effect of ARE 1 12 on motor function was also examined. Motor function was assessed by using automatic locomotive activity boxes. The animals were placed in a standard rodent box surrounded by photocell, which showed automatic recording of motor activity. The animals were found under motivational limitations and were free to move around the box. Male Sprague-Dawley rats (n = 4-9 per dose) were administered ARE 12 (IP) before placement in boxes of locomotor activity. The data are presented in Figure 8. Based on the data, it can be concluded that ARE 1 1 2 does not affect the locomotor activity when the animals were exposed to boxes of locomotor activity for 1.5 hours immediately after the injection of ARE 1 12. Although the data support the conclusion that ARE 1 1 2 reduces locomotor activity in rats 1 6 hours after injection (see, Figure 8), indicating that ARE 1 1 2 has some sedative activity, (for example, animals seem relaxed and show little or no behavior similar to anxiety), this sedative activity is moderate and can not, in and of itself, be considered for the reduction of food intake. As additional evidence in this moderate sedative activity, the animals were measured to determine their startle reflexes. In this analysis, ARE 1 12 was administered orally in rats not deprived of food 4.5 hours before the test. The animals were subjected to a pre-pulse of 12db followed by a pulse of 12db and subsequently measured for the height at which the animals jumped. Figure 1 2 shows the average startle amplitude of rats administered (ie, at 6.75, 13.5 g, 54 mg / kg). Rats treated at 3.5 and 54 mg / kg did not jump as high, compared to vehicle rats and rats treated at the lower dose of 6.75 mg / kg, impulse response. These data also suggest that in a higher dose of ARE 1 2, the animals show a moderate sedative activity. 5. Oral Availability: ARE1 12 Based on the developed in vivo data, the oral bioavailability of compound ARE 1 12 was determined. The compound was administered by oral priming at doses ranging from 6.75 to 54 mg / kg. The data presented in Figures 9A and 9B support the conclusion that oral administration of ARE 1 12 also reduces food intake in both food-deprived and non-food-deprived rats. The effect of ARE 1 12 depends on the dose and is compared with the effect observed after IP administration. In Figure 9A, the rats were deprived 24 hours before oral administration of the compound. In this analysis, the rats treated with the vehicle in 2.5 hours consumed approximately 6 grams of food while the injected rats consumed; particularly rats administered with 27 and 54 mg / kg of ARE1 12, they ate approximately 6 to 4 grams, respectively. As time passed, the vehicle rat consumed significantly more, approximately 14 grams 8 hours after administration, while the treated rats (at 27 and 54 mg / kg) consumed approximately 8 grams and 6 grams, respectively. (See, Figure 9A). In a second analysis, the rats were treated with ARE 1 1 2 by oral fattening but were not deprived of food. The data show a greater reduction in food intake, so that 18 hours after the administration of the compound, the vehicle rats consumed approximately 1.5 grams of food while the injected rats (in all doses) ate 5 grams or less; approximately a three-fold reduction in food consumption when treated with ARE1 12. (See, Figure 9B). These data support the conclusion that ARE 1 12 is orally active. 6. Evaluation of Other Compounds Several other inverse GPR6 agonists were also assessed under private food conditions for 24 hours, with administration PO. The analogs listed below were tested at 200 μmol / kg, which is equivalent to 54 mg / kg. In addition, ARE 1 14 was also evaluated at 1 00 μmol / kg (27 μmol / kg). The data is summarized below in Table C. TABLE C In a second analysis, tested under the same conditions, several other analogs were evaluated at 1 00 μmol / kg. The data is summarized below in Table D. TABLE D In Figure 10, the rats were deprived 24 hours prior to oral administration of the compound. In this analysis, the analogs ARE 1 30, ARE 1 35, ARE 1 36 and ARE 140 were administered in a dose of 1 00 μmol / kg. Three analogues, particularly ARE 1 30, ARE 1 36 and ARE 140 evidenced a slow food intake (for example, approximately 1 to 1.5 grams every two hours) for a period of time of eight hours after administration; while the rat vehicle consumed approximately 2 to 2.5 grams of feed every two hours. Similar to the vehicle rat, the analogue ARE 135, an open annular structure, evidenced that during a period of eight hours after administration the rats increasingly consumed approximately 2.5 grams every two hours (See, Figure 10A). In addition, the body weight of the vehicle rat and the rats administered with the analogue ARE 1 35 gained approximately 9.5 grams. On the other hand, closed ring structures showed a reduction in body weight gain as follows: ARE 1 12-6 grams, ARE 130-9 grams; ARE 1 36-1 1 grams and ARE4140-14 grams. See, Figure 10C. The treated rats, particularly ARE130 and ARE136, drank less amount of water compared to the animal vehicle, ie, approximately 10 grams and 4 grams less, respectively; while the analogs ARE 135 and ARE140 drank a comparable amount (i.e., approximately 19 grams). See, Figure 1 0B. These data suggest that closed ring structures, preferably ARE 1 12, ARE 136 and ARE 140; more preferably ARE1 12 and ARI? 130; and more preferably ARE1 12, are specific for the coupled G protein receptor. Table E below lists several IC5o values for the analogs of ARE 1 12. The IC5o values were derived using the GTP Analysis as described in Example 4A. At low concentrations of analogs ARE130, ARE136 and ARE140, GPR6 is activated, thus stimulating the conversion of GTP to GDP. These data support the suggestion that closed ring structures are selective inverse agonists for GPR6. TABLE E EXAMPLE 7 INVENTORY GPR6 AGONISTS Based on the present disclosure and the information provided herein, one of ordinary experience in the field is credited with the ability to directly identify candidate compounds as inverse agonists, agonists and partial agonists for GPR6. More preferably, these will be small molecule compounds that do not have evidence of those characteristics (ie, selective for GPR6) before such direct identification. For agonists, the objective in this selection is to find small molecules that increase the measured signal. Below, we describe our most preferred small molecule inverse GPR6 agonists. It is recognized that various stereoisomeric forms of the compounds described herein may exist. It is proposed that the present invention include racemates, individual enantiomers and mixtures thereof. 1 . Open Chain Aryl Series As a first series of GPR6 reverse agonists, "open chain arils" represented structurally as follows are described (note: if the selection of one or more of R8, R9, R10 and R11 results in a molecule Asymmetric or diastereomeric, then the racemic mixtures, the diastereomeric mixtures and each of the separated (+) and (-) enantiomers or diastereomers are within the scope of the series described, and within the scope of the following claims: R1, R2, R3, R4 and R5 are each selected independently of the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR15COR12, NR15SO2R12, OR12 , OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR1) 3, PO (OR12) 2R12, NO2, CN, C NR1 5 (NR1 3R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH, CH2CH CH2, CH CH2, SCH2S, SCH CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R6 and R7 are each independently selected from H, branched alkyl straight chain alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, straight chain alkyl C ^ s, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl C? -8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C .9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R14, (CH2) mSO3H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl C ^ s, branched alkyl, C2.8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, and CH2aryl, wherein each of said group on a ryl or said portion of aryl of said CH2aryl group can be optionally substituted by up to four substituents at any position on said aryl, each said position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3 , N (CH3) 2, N HC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, MHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC H7, SC H9, SCsHg, SC5H1 1 SCßHn, SC6H13, SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H 5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON ( CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain an aryl ring, said aryl ring being replaced in two adjacent positions in said aryl ring, then said two adjacent positions can be joined by a selected chain CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; or R13 and R14 can be part of a cyclic structure of 5, 6 or 7 members which can be either saturated or unsaturated and which can contain up to four heteroatoms selected from O, N, and S and said cyclic structure can be optionally substituted by up to four substituents at any position selected independently from F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, N HCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, N HSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCeHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC H9, SCsHg, SC5H1 1, SCeHn, SC6H13, SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SC OC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN , COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH 2, CONHCH 3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, or wherein when R13 and R14 form a ring substituted aryl in two adjacent positions in said aryl ring, then said two adjacent positions can be joined by a selected chain CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a structure bi-cyclical; and R15 is selected from H, straight chain alkyl d-β, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2.8 alkenyl. The following provisions, preferably observed, can be applied when R6, R7, R8, R9, R10 and R11 are all H, then at least one of R1, R2, R3 and R4 is different from H, and when R1, R2, R4, R5, R6, R7, R8, R9, R10 and R11 are all H, then R3 is not Cl, CH3, or OCH3; and when R1, R5, R6, R7, R8, R9, R10 and R11 are all H, then R2, R3 and R4 are not OCH3. An "aryl portion" can be a 5- or 6-membered aromatic heterocyclic ring (containing up to four heteroatoms independently selected from N, O or S) or a six-membered aromatic non-heterocyclic ring or a polycycle. Examples of suitable C? 8 alkyl groups include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Throughout this specification, the term "alkylaryl" is intended to mean alkyl portions having an aryl moiety attached thereto, for example benzyl groups. Examples of 5 or 6 membered ring portions include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycycle moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl and benzothienyl. Further described is a method for modulating the GPR6 receptor by contacting a receptor with a small molecule structurally represented as follows: wherein R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR, 3R14, NR1 5COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR 2, SO3R12, SO2NR13R14, PO (OR1) 3, PO (OR12) 2R12, NO2, CN, CNR1 5 (NR1 3R14), CNR1 5 (SR12), COOR12, COSR12, CONR13R14, and where either of two adjacent positions of R \ R2, R3, R4 and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R6 and R7 are each independently selected from H, C1-8 straight chain alkyl, branched alkyl, C3_8 cycloalkyl, cycloalkylalkyl or C4g alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, C1-8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d-8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2-8 alkenyl, aryl, alkylaryl, (CH2) nNR13R14, (CH2) mSO3H, and ( CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, and CH2aryl, wherein each of said group at ryl or said portion of aryl of said CH2aryl group can be optionally substituted by up to four substituents at any position on said aryl, each said position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3 , N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, N HCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, N HSO2C4H9 OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9 > OC5H9, OC5Hn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC H, SC4H9, SCsHg, SC5H 1 1, SCdHn, SCßH? 3 , SCF3, SCOCH3) SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2N HCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N ( C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CON HC H3, CO N (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7 ) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain an aryl ring, said aryl ring being substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a CHCHCHCH chain, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; or R13 and R14 may be part of a cyclic structure of 5, 6 or 7 members which may be either saturated or unsaturated and which may contain up to four heteroatoms selected from O, N, and S and said cyclic structure may optionally be substituted for up to four substituents in any selected position independently of: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7 , N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5Hn, OC6Hn , OC6H1-3, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SCsHg, SC5H1 1, SCßHn, SC8H? 3, SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7 , COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, or where when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, C? -8 straight chain alkyl, branched alkyl, C3. cycloalkyl, cycloalkylalkyl or C .9 alkylcycloalkyl and C2.8 alkenyl. 2. Closed chain aryl series A second series of GPR6 reverse agonists are "closed chain arils" represented structurally as follows: wherein R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR3R14, NR15COR12, NR15SO2R12 , OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR1 2, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR 1 5 (NR 13R14), CNR15 (SR12), COOR12, COSR12, CONR1 3R14, and wherein any two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2 , CH2CH2CH2 > CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; R8, R9, R10 and R11 are each independently selected from H, straight chain alkyl C? -8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d-8 > branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R? 4, (CH2) mSO3H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl d-8, branched alkyl, C2.8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, and CH2aryl, wherein each of said group on a rile or said portion of The aryl of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5 , N (C2H5) 2, NHC3H7, N (C3H7) 2l NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3 > NHSO2C2H5, NHSO2C3H7, N HSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCeH n, OC6H1 3, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3 , SC2H5, SC3H7, SC4H7, SC4H9, SCsHg, SC5H 1 1, SCßHi i, SC8H? 3, SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2N HCH3, SO2N (CH3) 2, SO2N HC2H5, SO2N (C2H5) 2, SO2N HC3H7, SO2N (C3H7) 2, SO2NHC4H9 , SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7 ) 2, WITH HC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be linked by a selected chain of CHCHCHCH , CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 may be part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents in any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3 ) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5 , OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCeHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SCsHg, SC5H1 1, SCßH n, SC8H? 3, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2N HCH3, SO2N (CH3) 2, SO2N HC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2N HC4H9 , SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, WITH HCH3, CON (CH3) 2 l CONHC2H5, CON (C2H5) 2, WITH HC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, C?-8 straight chain alkyl, branched alkyl, C; ¡8 cycloalkyl, cycloalkylalkyl or Ccg alkylcycloalkyl and C2.8 alkenyl. The following provisions, preferably observed, can be applied when R6, R7, R8, R9, R10 and R11 are all H, then at least one of R1, R2, R3 and R4 is different from H, and when R1, R2, R4, R5, R6, R7, R8, R9, R10 and R11 are all H, then R3 is not Cl, CH3, or OCH3; and when R1, R5, R6, R7, R8, R9, R10 and R11 are all H, then R2, R3 and R4 are not OCH3. An "aryl portion" can be a 5- or 6-membered aroc heterocyclic ring (containing up to four heteroatoms independently selected from N, O or S) or a non-heterocyclic to a 6-membered ring or a polycyclic ring. Examples of suitable C? 8 alkyl groups include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Examples of 5 or 6 membered ring portions include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycyclic portions include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl and benzothienyl. Further described is a method for modulating the GPR6 receptor by contacting said receptor with a small molecule structurally represented as follows: wherein R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br , I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR5COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any of two adjacent positions of R1, R2 , R3, R4 and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R8, R9, R10 and R11 are each independently selected from H, straight chain alkyl d-8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R 12 is selected from H, C?. 8 straight chain alkyl, branched alkyl, C3 8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2-8 alkenyl, aryl, alkylaryl, (CH2) nNR13R14, (CH2) mSO3H, and ( CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, C? .8 straight chain alkyl, branched alkyl, C2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH2aryl, wherein each of said aryl group or said portion of The aryl of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5 , N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, MHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7 l OC4H9, OC5H9, OC5Hn, OCeHn, OC6H13, OCF3, OCOCH3, OCOC2H5) OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5Hn, SC6Hn, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2Hs, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, S O2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON ( C3H7) 2, WITH HC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 can be part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and in wherein each said cyclic structure can optionally be replaced by up to four substituents in any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCgHn, OCeHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SCsHg, SC5H11, SCeHn, SC8H? 3, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7 , SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5 ) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl C? .8, branched alkyl, C3.3 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2-8 alkenyl; 3. Open chain 6-membered heteroaryl series A third series of GPR6 reverse agonists are "open chain 6-membered heteroaryls" structurally represented as follows: where at least one of V, W, XY and Z is selected from N and each of V, W. X, Y and Z which is / are not N are independently selected from CR1, CR2, CR3, CR4 and CR5, with the provision that at least two of V, W, X, Y and Z are different from N; R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR1 3R14, NR15COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR1 3R14, PO (OR12) 3, PO (OR1) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any of two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2 , SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R8, R9, R10 and R11 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R 12 is selected from H, straight chain alkyl d 8, branched alkyl, C 3-8 cycloalkyl, cycloalkylalkyl or C 1-9 alkylcycloalkyl) C 2 alkenyl, aryl, alkylaryl, (CH 2) n NR 13 R 4, (CH 2) m SO 3 H , and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl C? -8, branched alkyl, C2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH2aryl, wherein each of said aryl group or said portion of aryl of said CH2aryl group can be optionally substituted by up to four substituents at any position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCeHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC H7, SC4Hg, SCgHg, SC5H1 1, SCßH- i, SC8H3, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, S02NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2 , SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2) CONHC2H5, CON (C2H5) 2, CONHC3H7, CON ( C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be linked by a selected chain of CHCHCHCH , CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 are part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents in any position, each position selected independently of: F, Cl, Br, I, CF3, CCI3 > CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 NHC2H5, N (C2H5) 2, NHC3H7 l N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5 NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9 OCsHn, OCeHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9 OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7 SC4H7, SC4H9, SC5H9, SCsHn, SC6Hn, SC6H13, SCF3, SCOCH3, SCOC2H5 SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2 S02NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7 SO2N (C3H7 ) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5 COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2 CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2 WITH HC4H9, CON (C4H9) 2) and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be linked by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl d.8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.g alkylcycloalkyl and C2.8 alkenyl; A portion of aryl may be a 5- or 6-membered aromatic heterocyclic ring (containing up to four heteroatoms independently selected from N, O or S) or a non-heterocyclic 6-membered aromatic ring or a polycycle. Examples of suitable C? -8 alkyl groups include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Examples of 5 or 6 membered ring portions include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolium, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycycle moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl and benzothienyl. A method for modulating the GPR6 receptor by contacting said receptor with a small molecule structurally represented by the 6-membered heteroaryl series of the above open structure is further described. 4. Closed chain 6-membered heteroaryl series A fourth series of GPR6 reverse agonists are "closed chain 6-membered heteroaryls" structurally depicted as follows: wherein at least one of V, W, XY and Z is selected from N and each of V, W. X, Y and Z which is / are not N are independently selected from CR1, CR2, CR3, CR4 and CR5, with the provision that at least two of V, W, X, Y and Z are different from N; R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12 N R13R14, NR1 5COR12, NR1 5SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12 OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12 SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN CNR15 (NR13R14), CNR 5 (SR12), COOR12, COSR12, CONR13R14, and where either of two adjacent positions of R1, R2 R3, R4 and R5 can be joined by a selected chain of CHCHCHCH CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S OCH2O and OCH2CH2O to form a bi-cyclic structure; R8, R9, R10 and R1 i are each independently selected from H straight chain alkyl d-8, branched alkyl, C3.8 cycloalkyl cycloalkylalkyl or C4-9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d-8, branched alkyl C3-8 cycloalkyl, cycloalkylalkyl or C9 alkylcycloalkyl, C2.8 alkenyl aryl, alkylaryl, (CH2) nNR? 3R14, (CH2) mSO3H, and ( CH2) mCO2H where n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl C? 8, branched alkyl, C2.8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH2aryl, wherein each of said aryl group or said portion of The aryl of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5 , N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7 , OC4H9, OC5H9, OCsHn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5H1, SCßH-n, SC8H? 3, SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, S O2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON ( C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a selected chain of CHCHCHCH , CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents at any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , N HC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, N HSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5 , OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H, SC4H9, SCsHg, SC5H1 1, SCßH n, SCeH-o, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7 >; CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a selected chain of CHCHCHCH , CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl d.8 l branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C .9 alkylcycloalkyl and C2.8 alkenyl; A portion of aryl may be a 5- or 6-membered aromatic heterocyclic ring (containing up to four heteroatoms independently selected from N, O or S) or a non-heterocyclic 6-membered aromatic ring or a polycycle. Examples of suitable C? -8 alkyl groups include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Examples of 5 or 6 membered ring portions include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycycle moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoqinolyl, indolyl, quinoxalinyl, quinazolinyl and benzothienyl. Further described is a method for modulating the GPR6 receptor by contacting said receptor with a small molecule structurally represented by the above closed chain 6-membered heteroaryl series. 5. Heteroaryl of 5 open chain members (sub-series a). A fifth series of GPR6 inverse agonists are "open chain 5-membered heteroaryls" represented structurally as follows: wherein Z is selected from NR4, O, and S; W, X or Y are independently selected from N, CR1, CR2 and CR3, with the provision that when Z is O and Y is N, then W is CR1 and X is CR2.

R1, R2 and R3 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR15COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR1 5 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR 3R14, and wherein any two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a selected chain of CHCHCHCH, CH CH2CH2CH2, CHCHCH2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH S, SCH CH 2 S, OCH 2 O and OCH 2 CH 2 O to form a bi-cyclic structure; R 4 is selected from H, straight chain alkyl C 8, branched alkyl, C 3-8 cycloalkyl, cycloalkylalkyl or C 9 alkylcycloalkyl, C 2-8 alkenyl, aryl, alkylaryl, COR 5, CSR 5 and SO 2 R 5; R5, R6 and R7 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, straight chain alkyl d-8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl C? .8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R? , (CH2) mSO3H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, C? .8 straight chain alkyl, branched alkyl, C2.8 cycloalkyl or alkenyl, or alkylcycloalkyl, cycloalkylalkyl, or aryl and CH2aryl, wherein each of said aryl group or said Aryl portion of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position of: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , N HC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9 l N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5H1, 7 OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SCjHn, SC6H1 1 ? SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, S03C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N ( C4H9) 2, NO2, CN, COOCH3) COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, WITH HCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2 , CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R4 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions may be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2 > CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents at any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, N HSO2C4H9 l OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OC6H n, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H, SC4H9, SC5H9, SC5H1, SCSHn, SC8H3, SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, S03C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and where when R13 and R14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a two-dimensional structure. cyclical; and R15 is selected from H, C? .8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C8 alkenyl; A portion of aryl may be a 5- or 6-membered aromatic heterocyclic ring (containing up to four heteroatoms independently selected from N, O or S) or a non-heterocyclic 6-membered aromatic ring or a polycycle. Examples of suitable C? -8 alkyl groups include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Examples of 5 or 6 membered ring portions include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycycle moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl and benzothienyl. Further described is a method for modulating the GPR6 receptor by contacting said receptor with a small molecule structurally represented by the above open chain 5-membered heteroaryl series. 6. Heteroaryl with 5 closed chain members (sub-series a). A sixth series of GPR6 inverse agonists are "closed chain 5-membered heteroaryl sub-series" structurally represented as follows: wherein Z is selected from NR4, O and S; W, X or Y are independently selected from N, CR1, CR2 and CR3, with the provision that when Z is O and Y is N, then W is CR1 and X is CR2.

R1, R2 and R'1 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR1 5COR12, NR 5SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any of two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2 , SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R4 is selected from H, straight chain alkyl d-8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2-8 alkenyl, aplo, alkylaryl, COR5, CSR5 and SO2R5; R5, R6 and R7 are each independently selected from H, straight chain alkyl d.8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, C? .8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, straight chain alkyl d-8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R 12 is selected from H, straight chain alkyl C 8, branched alkyl, C 3-8 cycloalkyl, cycloalkylalkyl or C 9 alkylcycloalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2) n NR 13 R 14, (CH 2) m SO 3 H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl d_8, branched alkyl, C2-8 cycloalkyl or alkenyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl and CH2aryl, wherein each of said aryl group or said portion of The aryl of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5 , N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7 , OC4H9, OC5H9, OCsH,,, OC6H ", OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC6H? ? , SC6Hn, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, S02N (C3H7) 2, SO2NHC4H9 , SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7 ) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be linked by a selected CHCHCHCH chain, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents in any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCjHn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5 , OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SCsHn, SdHn, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3 ) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3 , CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions in said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, C? -8 straight chain alkyl, branched alkyl, C3 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2.8 alkenyl; A portion of aryl may be a 5- or 6-membered aromatic heterocyclic ring (containing up to four heteroatoms independently selected from N, O or S) or a non-heterocyclic 6-membered aromatic ring or a polycycle. Examples of suitable C? 8 alkyl groups include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Examples of 5 or 6 membered ring portions include, but are not limited to, phenyl, furanyl, thienyl, imidazole, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycycle moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl and benzothienyl. Further described is a method for modulating the GPR6 receptor by contacting said receptor with a small molecule structurally represented by the above closed chain 5-membered heteroaryl series. 7. Heteroaryl with 5 open chain members (sub-series b). As a seventh series of GPR6 reverse agonists, "open-chain 5-membered heteroaryl b-subsets" are represented structurally represented as follows: where Y is selected from NR4, O and S; W, X or Z are independently selected from N or CR1, CR2 or CR3, with the provision that when Y is O and Z is N, then W is CR1 and X is CR2 R1, R2 and R3 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR 3R14, NR15COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR 2) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and where either of two adjacent positions of R, R, R3, R4 and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; R4 is H, straight chain alkyl C8-8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, COR5, CSR5 and SO2R5; R5, R6 and R7 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R 2 is selected from H, straight chain alkyl d.8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C .9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R M, (CH2) mSO3H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl d-8, branched alkyl, C2.8 cycloalkyl or alkenyl, or alkylcycloalkyl, cycloalkylalkyl, or aryl and CH2aryl, wherein each of said aryl group or said portion of aryl of said CH2aryl group can be optionally substituted by up to four substituents at any position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCßHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H, SC4H9, SCsH, SC5H1 1, SCßHn, SC8Hi3 , SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2 , SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H1, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and in wherein each said cyclic structure can optionally be replaced by up to four substituents in any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, N HCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsH n, OCehln, OC6H1 3, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3 , OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SCsHg, SC5H1 1, S CTH H, SC8H3L SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHC H3, CON (CH3) 2, WITH HC2Hs, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, wherein when R13 and R14 form a substituted aryl ring at two adjacent positions in said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, C1-8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2.8 alkenyl; A portion of aryl may be a 5- or 6-membered aromatic heterocyclic ring (containing up to four heteroatoms independently selected from N, O or S) or a non-heterocyclic 6-membered aromatic ring or a polycycle. Examples of suitable C? -8 alkyl groups include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Examples of 5 or 6 membered ring portions include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycycle portions include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl and benzothienyl. Further described is a method for modulating the GPR6 receptor by contacting said receptor with a small molecule structurally represented by the above open chain 5-membered heteroaryl series. 15 8. Heteroaryl with 5 closed chain members (sub-series b). As an eighth series of GPR6 reverse agonists, "closed chain 5-membered heteroaryl b sub-series" are depicted structurally as follows: where Y is selected from NR4, O and S; W, X or Z are independently selected from N or CR1, CR2 or CR3, with 25 a provision that when Y is O and Z is N, then W is CR1 and X is ______ CR R1, R2 and R3 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR15COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; R 4 is selected from H, straight chain alkyl C 8, branched alkyl, C 3-8 cycloalkyl, cycloalkylalkyl or C 4-9 alkylcycloalkyl, C 2-8 alkenyl, aryl, alkylaryl, COR 5, CSR 5 and SO 2 R 5; R5, R6 and R7 are each independently selected from H, straight chain alkyl d-8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, C? .8 straight chain alkyl, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C-9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, straight chain alkyl C? 8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R 12 is selected from H, straight chain alkyl C 8, branched alkyl, C 3-8 cycloalkyl, cycloalkylalkyl or C 1-9 alkylcycloalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2) n NR 13 R 4, (CH 2) m SO 3 H , and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl C? 8, branched alkyl, cycloalkyl or C2-8 alkenyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl and CH2aryl, wherein each of said aryl group or said aryl portion of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position of: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3 > N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5Hn, OCSHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SCsHn, SCßHn, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3I SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9 , SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7 r COOC4Hβ, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2 l CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7 ) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a selected chain of CHCHCHCH , CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S , SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents at any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCssH n, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H, SC4Hg, SCsHg, SC5H1 1, SC8H? ? , SCßHi 3, SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2N H2, SO2N HCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, WITH HCH3, CON (CH3) 2, WITH HC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a selected chain of CHCHCHCH , CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl d.8, branched alkyl, C2 cycloalkyl, -8, cycloalkylalkyl or C12 alkylcycloalkyl and C2.8 alkenyl; A portion of aryl may be a 5- or 6-membered aromatic heterocyclic ring (containing up to four heteroatoms independently selected from N, O or S) or a non-heterocyclic 6-membered aromatic ring or a polycycle. Examples of suitable C? -8 alkyl groups include, but are not limited to methyl, ethyl, n-propyl, 1-propyl, n-butyl and t-butyl. Examples of 5 or 6 membered ring portions include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycycle moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolinyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl and benzothienyl. Further described is a method for modulating the GPR6 receptor by contacting said receptor with a small molecule structurally represented by the closed chain 5-member heteroaryl sub-series above. EXAMPLE 8 SYNTHETIC APPROACH The compounds described in this invention can be easily prepared according to a variety of synthetic manipulations, all of which would be familiar to one skilled in the art. In the general syntheses set forth below, the substituents labeled "R" have the same identifications as are established in the definitions of the compounds described below. (l) (!) (III) (I i HCl NH 4 OH EtOH. rt (V) In the approaches described below, "Procedure A" is the synthetic approach to formula (III), and "Procedure B" is the synthetic approach to formula (V). It is noted that in each of these approaches, the compound produced by Process A is in turn used as the starting material for the compound produced by Process B. The compounds of formulas (III) and (V) or a Solvate or physiologically functional derivative thereof can be used as active ingredients in pharmaceutical compositions, specifically as a GPR6 inverse agonist. The data developed herein supports the conclusion that inverse GPR6 agonists are of use for the treatment or prophylaxis of clinical obesity or overweight disorders in mammals, including, but not limited to, human. The compounds of the formulas (III) and (IV) can be administered by oral, sublingual, parenteral, rectal, topical administration by a transdermal patch. The transdermal patches distribute a drug at a controlled rate by presenting the drug for absorption in an effective manner with minimal degradation of the drug. Typically, the transdermal patches comprise an imperle backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner. Someone with ordinary experience in the field understands and appreciates the appropriate techniques to make an effective transdermal patch based on the needs of the artist. In addition to the neutral forms of the compounds of the formulas (III) and (V) by the appropriate addition of an ionizable substituent, which does not alter the specificity of the compound receptor, the physiologically acceptable salts of the compounds can also be formed and used as therapeutic agents. The different amounts of the compounds of the formulas (III) and (V) will be required to achieve the desired biological effect. The amount will depend on the factors such as the specific compound, the use for which it is proposed, the s of administration, and the condition of the individual treated, all of these dose parameters are within the level of an expert in the field in question. the medicinal arts. A typical dose can be expected to fall in the range of 0.001 to 200 mg per kilogram of body weight of the mammal. The single doses may contain from 1 to 200 mg of the compounds of the formula (III) or (V) and may be administered one or more times per day, individually or in multiples. In the case of the salt or solvate of a compound of the formulas (III) and (V), the dose is based on the cation (for salts) or the unsolvated compound. The compositions, including, but not limited to, pharmaceutical compositions, comprising at least one compound of the formulas (III) and (V) and / or a solvate or acceptable salt thereof (eg, a solvate or pharmaceutically acceptable salt) as an active ingredient combined with at least one vehicle or excipient (eg, excipient or pharmaceutical carrier). The pharmaceutical compositions can be used in the treatment of clinical conditions for which an inverse agonist of GPR6 is indicated. At least one compound of the formula (III) and (IV) can be combined with the carrier in either liquid or solid form in a single dose formulation. The pharmaceutical carrier must be compatible with the other ingredients in the composition and must be tolerated by the individual recipient. Other physiologically active ingredients can be incorporated into the pharmaceutical composition of the invention if desired, and if such ingredients are compatible with other ingredients in the composition. The formulations can be prepared by any suitable method, typically by uniformly mixing the active compound (s) with liquids or finely divided solid carriers., or both, in the required proportions, and then, if necessary, form the resulting mixture in a desired manner. Conventional excipients, such as binders, fillers, acceptable humectants, tabletting lubricants, and disintegrants can be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, oily or aqueous suspensions, and syrups. Alternatively, the oral preparations may be in the dry powder form which can be reconstituted with water or other non-aqueous vehicle before use. Parenteral dosage forms can be prepared by dissolving the compound of the invention in a suitable liquid carrier and filter sterilizing the solution prior to filling and sealing an appropriate vial or vial. These are just some examples of the many appropriate methods well known in the art for preparing dosage forms. It is observed that when inverse agonists are used GPR6 as active ingredients in a pharmaceutical composition, these are not intended to be used only in humans, but also in other non-human mammals. However, recent advances in the area of animal health care mandate that consideration be given for the use of inverse agonists of GPR6 in other domestic animals where disease or disorder is not evident (for example, animals for food such like cows, chickens, fish, etc.). Those of ordinary experience in the matter are easily credited with the usefulness of such compounds in such establishments. Below are the structural representations of the compounds that have been determined to show similar inverse agonist activity of similar PR6 G and selectivity as that of compound ARE 1 1 2.

ARE111 ARE112 ARE115 ARE116 AÜE117 ARE118 ARE119 ARE120 ARE121 ARE122 ARE123 ARE124 ARE 125 ARE126 ARE129 ARE130 ARE131 ARE132 ARE133 ARE134 ARE 135 ARE136 ARE 139 ARE140 ARE141 ARE142 ARE143 ARE144 ARE149 ARE150 ARE151 ARE152 ARE153 ARE154 EX EMPLOY 8B PR EPARATION OF COMPOUNDS ARE1 1 1 -ARE1 56 The mass spectra were recorded in mass spectrometer PE Sciex AP 150 EWX linked to a dual pump Shimadzu (two LC8 pumps) HPLC using a reverse phase column of C 1 8 CombiScreen (50 mm x 4.6 mm id). The gradient elution was for 5 minutes with 95% water containing 0.05% TFA) / 5% acetonitrile containing 0.35% TFA below 100% acetonitrile at a flow rate of 3.5 ml / min. Samples eluted from HPLC were routinely monitored at 220 nm using a Shimadzu SPD-1 0AVP detector unless otherwise stated. All reagents were purchased from commercial sources. Preparation 1 Preparation and Analysis of ARE 1 1 1 N- (2-thioxo-imidazolidine-1-carbothioyl) -thiophene-2-carboxamide and ARE 1 1 2 N-id.-dihydro-SH-imidazo ^ .l -cl -l ^^ - dithiazole-S-ylidene) -thiophene-2-carb oxamide The following synthetic procedures were used to generate each of the compounds below: Protocol AA a freshly prepared solution of potassium thiocyanate (2.14 g, 22 mmol) in dry acetone (80 ml), thiophene-2-carbonyl chloride (2.93 g, 20 mmol) was added dropwise at room temperature; the reaction mixture was then heated under reflux for 15 min to give thiophene-2-carbonyl isothiocyanate in situ as a yellow suspension. Heating was stopped and 2-imidazolidinationa (2.04 g, 20 mmol) was added. The mixture was then heated under reflux for an additional 4 hours before being allowed to cool followed by stirring at room temperature overnight (15 hours). 50 ml of water were added and the mixture was further stirred at room temperature for a few minutes. The resulting precipitate was collected by filtration and rinsed with water, water / methanol (1: 1) and methanol to give compound ARE 1 11 (2865 g, yield = 53%). Mass spectrum: m / z (%): 272.0 (M + H, 100) Calculated for C9HgN3OS2 = 27O.98 HPLC retention time: 2.97 min Protocol BA a suspension of ARE 1 1 1 (2g, 7.37 mmol) in Ethanol (30 ml) was added concentrated hydrochloric acid (0.75 ml) and 30% hydrogen peroxide (2 ml). The reaction mixture was heated under reflux in an oil bath for two hours while the yellow suspension turned white. The resulting precipitate was collected by filtration and rinsed with ethanol to give the hydrochloride salt which was then suspended in ethanol (20 ml) and treated with 28-30% ammonium hydroxide (1 ml) to yield the free base. The reaction mixture was stirred at room temperature for 20 min then the resulting precipitate was collected by filtration, rinsed with ethanol and dried to give compound ARE 12 (1,304 g, yield = 66%) as a yellowish solid. MS (ES +): m / z (%): 270 (M + H, 100) Mass spectrum: m / z (%): 270.0 (M + H, 100) Calculated for C9H7N3OS3 = 268.98 HPLC retention time: 2.36 min Preparation 2 Preparation and Analysis of ARE113 N- (2-thioxo-imidazolidine-1-carbothioyl) -benzamide and ARE114 N- (5,6-dihydro-3H) -imidazo [2,1-c] -1,2,4-dithiazole-3-ylidene) -benzamide The procedure of Protocol A above was followed, using benzoyl chloride instead of thiophene-2-carbonyl chloride, to produce ARE113 as a yellowish solid. Mass spectrum: m / z (%): 266.0 (M + H, 100) Calculated for C ?? H ?? N3OS2 = 265.02 HPLC retention time: 3.29 min Protocol B procedure was followed, using ARE113 instead of ARE 111, to produce ARE114 as a white solid. Mass spectrum: m / z (%): 263.8 (M + H, 61) Calculated for C? 2H? 2F3N3OS2 = 331.01 HPLC retention time: 2.53 min Preparation 3 Preparation and Analysis of ARE115 N- (2-thioxo- imidazolidine-1-carbothioyl) -4-trifluoromethylbenzamide and ARE116 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazole-3-yldene) -4- trifluoromethylbenzamide Protocol A was continued using 4- (trifluoromethyl) benzoyl chloride in place of thiophen-2-carbonyl chloride to produce ARE 1 15 as a yellowish solid. Mass spectrum: m / z (%): 173.0 (100), 334.2 (M + H, 83) Calculated for C12H10F3N3OS2 = 333.01 HPLC retention time: 3.69 min Protocol B was continued using ARE1 15 instead of ARE 1 1 1, to produce ARE 1 16 as a white solid. Mass spectrum: m / z (%): 332.0 (M + H, 1 00) Calculated for C1 1 H9F3N3OS2 = 331 .01 HPLC retention time: 3.28 min Preparation 4 Preparation and Analysis of ARE1 1 7 N- (2 -thioxo-imidazolidine-1-carbothioyl) -4-tert-butylbenzamide and ARE1 1 8 N- (5,6-dihydro-3H-imidazo [2,1-c] -1, 2,4-dithiazol-3-ylidene ) -4-tert-butylbenzamide Protocol A was continued using 4-tert-butylbenzoyl chloride instead of thiophene-2-carbonyl chloride to produce compound ARE 1 17 as a yellowish solid. Mass spectrum: m / z (%): 161 .0 (100), 322.0 (M + H, 53) Calculated for d5H19N3OS2 = 321 .45 HPLC retention time: 3.97 min Protocol B was continued using ARE 1 17 instead of ARE 1 1 1, to produce compound ARE1 18 as a white solid. Mass spectrum: m / z (%): 320.0 (M + H, 100) Calculated for C15H17N3OS2 = 319.45 HPLC retention time: 3.72 min Preparation 5 Preparation and Analysis of ARE1 19 N- (2-thioxo-imidazolidine-1) -carbotyoyl) -4-chlorobenzamide and ARE120 N- (5,6-dihydro-3H-imidazo [2,1-c] -1, 2,4-dithiazol-3-ylidene) -4-chlorobenzamide Protocol A was followed using 4-chlorobenzoyl chloride in place of thiophene-2-carbonyl chloride to produce compound ARE 1 19 as a yellowish solid. Mass spectrum: m / z (%): 1 39.0 (100), 300.0 (M + H, 56) Calculated for d? H? 0CIN3OS2 = 298.98 HPLC retention time: 3.52 min Protocol B was continued using ARE 1 1 9 instead of ARE 1 1 1, to produce compound ARE120 as a white solid. Mass spectrum: m / z (%): 139.0 (100), 298.0 (M + H, 72) Calculated for d? H18CIN3OS2 = 296.98 HPLC retention time: 3.01 min Preparation 6 Preparation and Analysis of ARE121 N- (2-t-ioxo-imidazolidine-1-carbothioyl) -4-methoxybenzamide and ARE 122 N-fS.e-dihydro-SH- imidazo ^ .l -cl- '^ -dithiazol-S-ylideneM-methoxybenzamide Protocol A was continued using 4-methoxybenzoyl chloride instead of thiophene-2-carbonyl chloride to produce compound ARE 121 as a yellowish solid.

Mass spectrum: m / z (%): 135.0 (100), 296.2 (M + H, 39) Calculated for C12H13N3? 2S2 = 295.03 HPLC retention time: 3.37 min Protocol B was continued using ARE 121 instead of ARE 1 1 1, to produce compound ARE 122 as a white solid. Mass spectrum: m / z (%): 294.0 (M + H, 100) Calculated for C? 2H1 1 N3O2S2 = 293.03 HPLC retention time: 2.89 min Preparation 7 Preparation and Analysis of ARE1 23 N- (2-1 : ioxo-imidazolidine-1-carbothioyl) -3-methoxybenzamide and ARE124 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,4, 2,4-dithiazole-3-ylidene ) -3-methoxy benzamide Protocol A was continued using 3-methoxybenzoyl chloride instead of thiophene-2-carbonyl chloride to produce compound ARE 123 as a yellowish solid. Mass spectrum: m / z (%): 135.2 (100), 296.2 (M + H, 53) Calculated for C12H? 3N3O2S2 = 295.03 HPLC retention time: 3.20 min Protocol B was continued using ARE 123 instead of ARE 1 1 1, to produce compound ARE 124 as a white solid. Mass spectrum: m / z (%): 294.0 (M + H, 100) Calculated for HPLC retention time: 2.94 min Preparation 8 Preparation and Analysis of ARE125 N- (2-thioxo-imidazolidine-1-carbothioyl) - 3-methylbenzamide and ARE1 26 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,4, 2,4-dithiazol-3-yldene) -3-methylbenzamide Protocol A 3-methylbenzoyl chloride was continued in place of thiophene-2-carbonyl chloride to produce compound ARE 125 as a yellowish solid. Mass spectrum: m / z (%): 1 1 9.4 (100), 280.0 (M + H, 47) Calculated for C12H? 3N3OS2 = 279.03 HPLC retention time: 3.59 min Protocol B was continued using ARE 125 in place of ARE 1 1 1, to produce compound ARE 126 as a white solid. Mass spectrum: m / z (%): 278.0 (M + H, 100) Calculated for C? 2H? ? N3OS2 = 277.03 HPLC retention time: 3.1 1 min Preparation 9 Preparation and Analysis of ARE127 N- (2-thioxo-imidazolidine-1-carbothioyl) -4-fluorobenzamide and ARE128 N- (5,6-dihydro-3H-imidazo) [2,1-c] -1, 2,4-dithiazol-3-ylidene) -4-fluorobenzamide Protocol A was continued using 4-fluorobenzoyl chloride instead of thiophene-2-carbonyl chloride to produce the compound ARE 127 as a yellowish solid. Mass spectrum: m / z (%): 123.2 (100), 284.2 (M + H, 75) Calculated for C1 1 H10FN3OS2 = 283.01 Protocol B was continued using ARE127 instead of ARE111, to produce compound ARE128 as a solid white. Mass spectrum: m / z (%): 123.2 (100) 282.2 (M + H, 90) Calculated for CnH8FN3OS2 = 281.01 HPLC retention time: 2.68 min Preparation 10 Preparation and Analysis of ARE129 N- (2-1: ioxo-imidazolidine-1-carbothioyl) -3-fluorobenzamide and ARE130 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -3-fluorobenzamide Protocol A was continued using 3-fluorobenzoyl chloride in place of thiophene-2-carbonyl chloride to produce compound ARE129 as a yellowish solid. Mass spectrum: m / z (%): 123.2 (100), 284.3 (M + H, 61) Calculated for d? H? 0FN3OS2 = 283.01 HPLC retention time: 3.24 min Protocol B was continued using ARE129 instead of ARE111, to produce compound ARE 130 as a white solid. Mass spectrum: m / z (%): 282.2 (M + H, 100) Calculated for d? H8FN3OS2 = 281.01 HPLC retention time: 2.97 min Preparation 11 Preparation and Analysis of ARE131 N- (2-t? Oxo- imidazolidine-1-carbothioyl) -2-fluorobenzamide and ARE132 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -2- fluorobenzamide The Protocol A continued to use 2-fluorobenzoyl chloride in place of thiophene-2-carbonyl chloride to produce compound ARE131 as a yellowish solid. Mass spectrum: m / z (%): 123.2 (100), 284.0 (M + H, 67) Calculated for d? H10FN3OS2 = 283.01 HPLC retention time: 3.07 min Protocol B was continued using ARE131 instead of ARE111, to produce compound ARE132 as a white solid. Mass spectrum: m / z (%): 282.2 (M + H, 100) Calculated for CnH8FN3OS2 = 281.01 HPLC retention time: 2.72 min Preparation 12 Preparation and Analysis of ARE133 N- (2-thioxo-imidazolidine-1-carbothioyl) -2,4-difluorobenzamide and ARE134 N- (5,6-dihydro-3H- imidazo [2,1-c] -1,2,4-dithiazole-3-idene) -2,4-d iflu or robe nza imida Protocol A was continued using 2,4-difluorobenzoyl chloride instead of chloride of thiophene-2-carbonyl to produce compound ARE133 as a yellow solid. Mass spectrum: m / z (%): 141.0 (100), 302.2 (M + H, 39) Calculated for CnH9F2N3OS2 = 301.00 HPLC retention time: 3.23 min Protocol B was continued using ARE133 instead of ARE111, for produce compound ARE134 as a white solid.

Mass spectrum: m / z (%): 300.0 (M + H, 100) Calculated for C11H7F2N3OS2 = 299.00 HPLC retention time: 2.86 min Preparation 13 Preparation and Analysis of ARE135 N- (2-thioxo-imidazolidine-1-) carbothioyl) -naphthyl-2-carboxamide and ARE136 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -naphthyl-2-carboxamide Protocol A was continued using 2-naphthoyl chloride instead of thiophene-2-carbonyl chloride to produce compound ARE135 as a yellowish solid. Mass spectrum: m / z (%): 155.0 (100), 316.0 (M + H, 56) Calculated for C15H13N3OS2 = 315.40 HPLC retention time: 3.88 min Protocol B was continued using ARE135 instead of ARE111, to produce compound ARE136 as a white solid. Mass spectrum: m / z (%): 314.0 (M + H, 100) Calculated for C? 5H11N3OS2 = 313.40 HPLC retention time: 3.41 min Preparation 14 Preparation and Analysis of ARE137 N- (2-thioxo-imidazolidine- 1-carbothioyl) -naphthyl-1-carboxamide and ARE138 N- (5,6-dihydro-3 H -amidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -naphthyl- 1 -carboxamide Protocol A was continued using 1-naphthoyl chloride instead of thiophene-2-carbonyl chloride to produce compound ARE 1 37 as a yellow solid. Mass spectrum: m / z (%): 155.0 (100), 316.0 (M + H, 39) Calculated for d5H? 3N3OS2 = 315.40 HPLC retention time: 3.80 min Protocol B was continued using ARE 1 37 instead of ARE1 1 1, to produce compound ARE138 as a white solid. Mass spectrum: m / z (%): 314.0 (M + H, 100) Calculated for C? 5H13N3OS2 = 313.05 HPLC retention time: 3.38 min Preparation 1 5 Preparation and Analysis of ARE1 39 N- (2-thioxo- imidazolidine-1-carbothioyl) -benzothiophen-2-carboxamide and ARE 140 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,4, 2,4-dithiazol-3-ylidene) -benzothiophen 2- carboxamide Protocol A was continued using benzo [b] thiophene-2-carbonyl chloride instead of thiophene-2-carbonyl chloride to produce compound ARE 139 as a yellowish solid. Mass spectrum: m / z (%): 160.8 (100), 321 .8 (M + H, 51) Calculated for C13Hn N3OS2 = 320.99 HPLC retention time: 3.92 min Protocol B was continued using ARE 139 instead of ARE 1 1 1, to produce compound ARE 140 as a white solid. Mass spectrum: m / z (%): 320.0 (M + H, 100) Calculated for C1 3H9N3OS2 = 31 8.99 HPLC retention time: 3.47 min Preparation 16 Preparation and Analysis of ARE 143 N- (2-thioxo-imidazolidine -1-carbotioyl) -furan-2-carboxamide and ARE144 N- (5,6-dihydro-3H-imidazo [2,1-c] -1, 2,4-dithiazole-3-ylidene) -furan- 2-carboxamide Protocol A was continued using 2-furoyl chloride instead of thiophene-2-carbonyl chloride to produce compound ARE143 as a yellowish solid. Mass spectrum: m / z (%): 256.0 (M + H, 100) Calculated for C9H9N3O2S2 = 255.00 HPLC retention time: 2.86 min Protocol B was continued using ARE 143 instead of ARE 1 1 1, to produce Compound ARE 144 as a white solid. Mass spectrum: m / z (%): 254.2 (M + H, 1 00) Calculated for C9H9N3O2S2 = 253.00 HPLC retention time: 2.1 3 min Preparation 17 Preparation and Analysis of ARE148 N-td.β-dihydro-SH -imidazo ^ .l -cl-l ^^ - dithiazol-S-ylidene) ^^ - dimethylisoxazole-4-carboxamide Protocol A was continued using 2-chloro, 5-dimethylisoxazole-4-carbonyl instead of thiophene-2-carbonyl chloride to produce N- (2-thioxo-imidazolidine-1-carbothioyl) -2,5-dimethylisoxazole-4-carboxamide as a yellowish solid. Protocol B was continued using the above compound instead of ARE 1 1 1, to produce compound ARE148 as a white solid. Mass spectrum: m / z (%): 283.0 (M + H, 1 00) Calculated for C10H1 0N4O2S2 = 282.02 HPLC retention time: 2.53 min Preparation 18 Preparation and Analysis of ARE 149 N- (2-thioxo-imidazolidine-1-carbothioyl) -isoxazole-3-carboxamide and ARE 150 N- (5,6-d) Hydro-3H-imidazo [2,1-c] -1, 2,4-dithiazol-3-yldene) -isoxazole-3-carboxamide Protocol A was continued using isoxazole-3-carbonyl chloride instead of thiophene-2-carbonyl chloride to produce compound ARE 149 as a yellowish solid. Mass spectrum: m / z (%): 257.0 (M + H, 100) Calculated for C8H8N4O2S2 = 255.99 HPLC retention time: 2.76 min Protocol B was continued using ARE 149 instead of ARE 1 1 1, to produce compound ARE 1 50 as a white solid. Mass spectrum; m / z (%): 255.2 (M + H, 1 00) Calculated for HPLC retention time: 2.09 min Preparation 1 9 Preparation and Analysis of ARE 1 51 N- (2-thioxo-imidazolidine-1-carbotium) ) -2- (4-chlorophenyl) -3- (trifluoromethyl) pyrazole-4-carboxamide and ARE152 N- (5,6-dihydro-3H-imidazo [2,1-c] -1, 2,4-dithiazole- 3-ylidene) -2- (4-chlorophenyl) -3- (trifluoromethyl) arazole-4-carboxamide Protocol A was continued using 2- (4-chlorophenyl) -3- (trifluoromethyl) pyrazole-4-carbonyl chloride in place of thiophene-2-carbonyl chloride to produce compound ARE151 as a yellowish solid. Mass spectrum: m / z (%): 273.0 (100), 434.0 (M + H, 76) Calculated for C1 5H1 1CIF3N4? 2S2 = 432.99 HPLC retention time: 4.25 min Protocol B was continued using ARE 1 51 instead of ARE 1 1 1, to produce compound ARE 1 52 as a white solid. Mass spectrum: m / z (%): 431 .8 (M + H, 100) Calculated for C1 5H9CIF3N5OS2 = 431 .8 HPLC retention time: 3.77 min Preparation 20 Preparation and Analysis of ARE1 53 N- (2- thioxo-imidazolidine-1-carbothioyl) -2- (4-chloro-phenyl) -3- (trifluoromethyl) -phenyl-4-carboxamide Protocol A was continued using 2-methyl-5-phenylisoxazole-4-carbonyl chloride instead of thiophene-2-carbonyl chloride to produce ARE 153 as a yellowish solid. Mass spectrum: m / z (%): 344.8 (100), (M + H, 100) Calculated for C15H12N4O2S2 = 344.42 HPLC retention time: 4.57 min Preparation 21 Preparation and Analysis of ARE154 N- (2-thioxo- imidazolidine-1-carbothioyl) -pyridine-2-methylthio-3-carboxamide Protocol A was continued using pyridine-2-methylthio-3-carbonyl chloride instead of thiophene-2-carbonyl chloride to produce ARE 1 54 as a yellowish solid . Mass spectrum: m / z (%): 1 52.2 (100), 313.2 (M + H, 100) Calculated for d? H12N4OS3 = 312.02 HPLC retention time: 3.31 min Preparation 22 Preparation and Analysis of ARE155 N- (2-thioxo-imidazolid ina-1-carbothioyl) -pyridine-3-carboxamide and ARE 156 N- (5,6- dihydro-3H-ylidazo [2, 1 -c] -1, 2,4-dithiazol-3-ylidene) -pi-di-na -3-carboxyamide Protocol A was continued using pyridine-3-carbonyl chloride instead of thiophene-2-carbonyl chloride to produce compound ARE 155 as a yellowish solid. Mass spectrum: m / z (%): 165.0 (100), 267.0 (M + H, 50) Calculated for C10H10N4OS2 = 266.03 HPLC retention time: 2.29 min Protocol B was continued using ARE155 instead of ARE 1 1 1, to produce compound ARE156 as a white solid. Mass spectrum: m / z (%): 265.0 (M + H, 100) Calculated for C? 0H8N4OS2 = 264.01 HPLC retention time: 1.87 min The different embodiments of the invention will consist of different constitutively active receptors, systems of expression, different analyzes, and different compounds. Those skilled in the art will understand which receptors are used with the expression systems and methods of analysis. Everything is considered within the scope of the teachings of this invention. In addition, those skilled in the art will recognize that various modifications, additions, substitutions and variations to the illustrative examples set forth herein may be made without departing from the spirit of the invention and are therefore considered within the scope of the invention. Nevertheless, with the analysis systems described above, as well as the relationship between the GPR6 receptor and feeding behavior, someone with ordinary experience in the field is easily credited with the ability to directly identify small molecule inverse agonists, agonists or partial agonists. to the recipient - for example, it is noted that the phrase "small molecule GPR6 invective agonist" is not limited to the specific compounds described herein. All patent documents, applications, and printed publications cited by this patent document, including provisional applications and regular patent applications, unless otherwise indicated, are hereby incorporated in their entirety for reference. The modifications and extension of the described inventions that are within the field of the skilled artisan are comprised within the above description and the claims that follow.

LIST OF SEQUENCES < 110 > Arena Pharmaceuticals, Inc. < 120 > Modulators of Small Molecule of Receptor Six Coupling of Protein G. < 130 > AREN0059 < 140 > PCT / US00 / 04945 < 141 > 2000-02-25 < 150 > 09 / 364,425 < 151 > 1999-07-30 < 150 > 60 / 094,879 < 151 > 1998-07-31 < 150 > 60/106, 300 < 151 > 1998-10-30 < 150 > 60 / 110,906 < 151 > 1998-12-04 < 150 > 60 / 121,851 < 151 > 1999-02-26 < 150 > 60 / 173,850 < 151 > 1999-12-30 < 150 > 60 / 174,428 < 151 > 2000-01-04 < 150 > 09 / 364,425 < 151 > 1999-07-30 < 160 > 6 < 170 > Patentln Ver. 2.1 < 210 > 1 < 211 > 1089 < 212 > DNA < 213 > Homo sapiens < 400 > 1 atgaacgcga gcgccgcctc gctcaacgac tcccaggtgg tggtagtggc ggccgaagga 60 gcggcggcgg cggccacagc agcagggggg ccggacacgg gcgaatgggg accccctgct 120 gcggsggctc taggagccgg cggcggagct aatqggtctc tggagctgtc ctcgcagctg 180 tcg'gctgggc fall-gggact cctgctgcca gc gtgaatc cgtgggacgt gctcctgtgc 240 gtgtcgggga cagtgatcgc tggagaaaac gcgctggtgg tggcgctcat cgcgtccact 300 ccggcgctgc gcasgcccat gttcgtgctg gtaggcagcc tggccaccgp tgacctgttg 360 gcgggctgtg gcctcatctt gcactttgtg ttccagtact tggtgccctc ggagactgtg 420 agtctgctca cggtgggctt cctcgtggcc tccttcgccg cctctgtcag cagcctgctg 480 gccattacgg tggaccgcta cctgtccctg tataacgcgc tcacctatta ctcgcgccgg 540 accctgttgg gcgtgcacct cctgcttgcc gccacttgga ccgtgtccct aggcctgggg 600 ctgctgcccg tgctgggctg gaactgcctg gcagagcgcg ccgcctgcag cgtggtgcgc 660 ccgctggcgc gcagccacgt ggctctgctc tccgccgcct tcttcatggt cttcggcatc 720 atgctgcacc tgtacgtgcg catctgccag gtggtctggc gccacgcgca ccagatcgcg 780 ctgcagcagc actgcctggc gccaccccat ctcgctgcca ccagaaaggg tgtgggtaca 840 ctggctgtgg tgctgg GCAC tttcggcgcc agctggctgc ccttcgccat ctattgcgtg 900 gtgggcagcc atgaggaccc ggcggtctac acttacgcca ccctgctgcc cgccacctac 960 aactccatga tcaatcccat catctatgcc ttccgcaacc aggagatcca gcgcgccctg 1020 tggctcctgc tctjtggctg tttccagtcc aaagtgccct ttcgttccag gtctcccagc gaggtctga 1080 1089 < 210 > 2 < 211 > 362 < 212 > PRT < 213 > Homo sapiens < 400 > 2 Met Asn Wing Be Wing Wing Ser Leu Asn Asp Ser Gln Val Val Val Val 1 5 10 15 Wing Wing Gly Wing Wing Wing Wing Wing Thr Wing Wing Gly Gly Pro Asp 20 25 30 Thr Gly Glu Trp Gly Pro Pro Wing Wing Wing Ala Leu Glv Ala Gly Gly 35 40 45 Gly Ala Asn Gly Ser Leu Glu Leu Ser Ser Gln Leu Ser Ala Gly Pro 50 55 60 Pro Gly Leu Leu Leu Pro Ala Val Asn Pro Trp Asp Val Leu Leu Cys 65 70 75 80 Val Ser Gly Thr Val lie Wing Gly Glu Asn Wing Leu Val Val Wing Leu 85 90 95 lie Wing Being Thr Pro Wing Leu Arg Thr Pro Met Phe Val Leu Val Gly 100 105 110 Ser Leu Wing Thr Wing Asp Leu Leu Wing Gly Cys Gly Leu lie Leu His 115 120 125 _ 'Phß Val Phe Gln Tyr Leu Val Pro Ser Glu Thr Val Ser Leu Leu Thr 130 135 140 Val Gly Phe Leu Val Ala Ser Phe Ala Ala Ser Val Ser Ser Leu Leu 145 150 155 160 Ala lie Thr Val Asp Arg Tyr Leu Ser Leu Tyr Asn Ala Leu Thr Tyr 165 170 175 Tyr Ser Arg Arg Thr Leu Leu Gly Val His Leu Leu Leu Ala Wing Thr 180 185 190 Trp Thr Val Ser Leu Gly Leu Gly Leu Leu Pro Val Leu Gly Trp Asn 195 200 205 Cys Leu Wing Glu Arg Wing Wing Cys Ser Val Val Arg Pro Leu Ala Arg 210 215 220 Ser His Val Ala Leu Leu Ser Ala Ala Phe Phe Met Val Phe Gly lie 225 230 235 240 Met Leu His Leu Tyr Val Arg lie Cys Gln Val Val Trp Arg His Ala 245 250 255 His Gln He Ala Leu Gln Gln His Cys Leu Wing Pro Pro His Leu Wing 260 265 270 Wing Thr Arg Lyß Gly Val Gly Thr Leu Wing Val Val Leu Gly Thr Phe 275 280 285 Gly Wing Ser Trp Leu Pro Phe Wing He Tyr Cy3 Val Val Gly Ser His 290 295 300 Glu Asp Pro Wing Val Tyr Thr Tyr Wing Thr Leu Leu Pro Wing Thr Tyr 305 310 315 320 Asn Ser Met He Asn Pro He He Tyr Wing Phe Arg Asn Gln Glu He 325 330 335 Gln Arg Ala Leu Trp Leu Leu Leu Cys Gly Cys Phe Gln Ser Lys Val 340 345 350 Pro Phe Arg Ser Arg Ser Pro Ser Glu Val 355 360 < 210 > 3 < 211 * 31 < 2Í2 > DNA < 213 > Homo sapiens < 400 > 3 gatctctaga atgcagggtg caaatccggc c 31 < 210 > 4 < 211 > 35 < 212 > DNA < 213 > Homo sapiens < 400 > 4 ctagggtacc cggacctcgc tgggagacct ggaac 35 < 210 > 5 < 211 > 2328 < 212 > DNA < 213 > Homo sapiens < 400 > 5 tctagaatgc agggtgcaaa tccggccgcg atgaacgcga gcgccgcctc gctcaacgac 60 tcccaggtgg tggtagtggc ggccgaagga gcggcggcgg cggccacagc agcagggggg 120 ccggacacgg gcgaatgggg accccctgct gcggcggctc taggagccgg cggcggagct 180 aatgggtctc tggagctgtc ctcgcagctg tcggctgggc caccgggact cctgctgcca 240 gcggtgaatc cgtgggacgt gctcctgtgc gtgtcgggga cagtgatcgc tggagaaaac 300 gcgctggtgg tggcgctcat cgcgtccact ccggcgctgc gcacgcccat gttcgtgctg 360 gtaggcagcc tggccaccgc tgacctgttg gcgggctgtg gcctcatctt gcactttgtg 420 ttccagtact tggtgccstc ggagactgtg agtctgctca cggtgggctt cctcgtggcc 480 tccttcgccg cctctgtcag cagcctgctg gccattacgg tggaccgcta cctgtccctg 540 tataacgcgc tcacctatta ctcgcgccgg accctgttgg gcgtgcacct cctgcttgcc 600 gccacttgga ccgtgtccct aggcctgggg ctgctgcccg tgctgggctg gaactgcctg 660 gcagagcgcg ccgcctgcag cgtggtgcgc ccgctggcgc gcagccacgt ggctctgctc 720 tccgccgcct tcttcatggt cttcggcatc atgctgcacc tgtacgtgcg catstgccag 780 gccacgcgca gtggtctggc ccagatcgcg ctgcagcagc actgcctggc gccaccccat 840 ctcgctgcca ccagaaag gg tgtgggtaca ctggctgtgg tgctgggcac tttcggcgcc 900 agctggctgc ccttcgccat ctattgcgtg gtgggcagcc atgaggaccc ggcggtctac 960 acttacgcca ccctgctgcc cgccacctac aactccatga tcaatcccat catctatgcc 1020 ttccgcaasc aggagatcca gcgcgccctg tggctcctgc tctgtggctg tttccagtcc 1080 aaagtgccct ttcgttccag gtctcccagc gaggtccggg taccaagctt gggctgcagg 1140 tcgatgggct gcctcggcaa cagtaagacc gaggaccagc gcaacgagga gaaggcgcág 1200 cgcgaggcca acaaaaagat cgagaagcag ctgcagaagg acaagcaggt ctaccgggcc 1260 acgcaccgcc tgctgctgct gggtgctgga gagtctggca aaagcaccat tgtgaagcag 1320 atgaggatcc tacatgttaa tgggtttaac ggagagggcg gcgaagagga cccgcaggct 1380 gcaaggagca acagcgatgg tgagaaggcc accaaagtgc aggacatcaa aaacaacctg 1440 aaggaggcca ttgaaaccat tgtggccgcc atgagcaacc tggtgccccc cgtggagctg 1500 gccaabcctg agaaccagtt cagagtggac tacattctga gcgtgatgaa cgtgccaaac 1560 tttgacttcc cacctgaatt ctatgagcat gccaaggctc tgtgggagga tgagggagtt 1620 cgtgcctgct acgagcgctc caacgagtac cagctgatcg actgtgccca gtacttcctg 1680 atgtgatcaa gacaagattg gc aggccgac tacgtgccaa gtgaccagga cctgcttcgc 1740 tgccgcgtcc tgacctctgg aatctttgag accaagttcc aggtggacaa agtcaacttc 1800 cacatgttcg atgtgggcgg ccagcgcgat agtggatcca gaacgccgca gtgcttcaat 1860 gatgtgactg ccatcatctt cgtggtggcc agcagcagct acaacatggt catccgggag 1920 gacaaccaga ccaaccgtct gcaggaggct ctgaacctct tcaagagcat ctggaacaac 1980 agatggctgc gtaccatctc tgtgatcctc ttcctcaaca agcaagatct gcttgctgag 2040 aaggtcctcg ctgggaaatc gaagattgag gactactttc cagagttcgc tcgctacacc 2100 actcctgagg atgcgactcc cgagcccgga gaggacccac gcgtgacccg ggccaagtac 2160 ttcatccggg atgagtttct gagaatcagc actgctagtg gagatggacg tcactactgc 2220 taccctcact ttacctgcgc cgtggacact gagaacatcc gccgtgtctt caacgactgc 2280 cgtgacatca tccagcgcat gcatcttcgc caatacgagc tgctctaa 2328 < 210 > 6 < 211 > 775 < 212 > PRT < 213 > Homo sapiens < 400 > 6 Be Arg Met Gln Gly Wing Asn Pro Wing Wing Met Asn Wing Wing Wing 1 5 10 15 Ser Leu Asn Asp Ser Gln Val Val Val Val Wing Wing Glu Gly Wing Wing 20 25 30 Wing Wing Thr Wing Wing Gly Wing Gly Pro Asp Thr Gly Glu Trp Gly Pro 35 40 45 Pro Wing Wing Wing Wing Leu Gly Wing Gly Gly Wing Wing Asn Gly Ser Leu 50 55 60 Glu Leu Ser Ser Gln Leu Wing Wing Gly Pro Pro Gly Leu Leu Pro 65 70 75 80 Wing Val Asn Pro Trp Asp Val Leu Leu Cys Val Ser Gly Thr Val He 85 90 95 Wing Gly Glu Asn Wing Leu Val Val Wing Leu He Wing Being Thr Pro Wing 100 105 110 Leu Arg Thr Pro Met Phe Val Leu Val Gly Ser Leu Ala Thr Ala Asp 115 120 125 Leu Leu Ala Gly Cys Gly Leu He Leu His Phe Val Phe Gln Tyr Leu 130 135 140 Val Pro Ser Glu Thr Val Ser Leu Leu Thr Val Gly Phe Leu Val Ala 145 150 155 160 Ser Phe Ala Ala Ser Val Ser Ser Leu Leu Ala He Thr Val Asp Arg 165 170 175 Tyr Leu Ser Leu Tyr Asn Wing Leu Thr Tyr Tyr Ser Arg Arg Thr Leu 180 185 190 Leu Gly Val His Leu Leu Leu Wing Wing Thr Trp Thr Val Ser Leu Gly 195 200 205 Leu Gly Leu Leu Pro Val Leu Gly Trp Asn Cys Leu Wing Glu Arg Wing 210 215 220 Wing Cys Ser Val Val Arg Pro Leu Wing Arg Ser His Val Wing Leu Leu 225 230 235 240 Be Wing Wing Phe Phe Met Val Phe Gly He Met Leu His Leu Tyr Val 245 250 255 Arg He Cys Gln Val Val Trp Arg His Ala His Gln He Ala Leu Gln 26C 265 270 Gln His Cys Leu Ala Pro Pro His Leu Ala Ala Thr Arg Lys Gly Val 275 280 285 Gly Thr Leu Ala Val Val Leu Gly Thr Phe Gly Ala Ser Trp Leu Pro 290 295 300 Phe Wing He Tyr Cys Val Val Gly Ser His Glu Asp Pro Wing Val Tyr 305 310 315 320 Thr Tyr Wing Thr Leu Leu Pro Wing Thr Tyr Aßn Ser Met He Asn Pro 325 330 335 He He Tyr Wing Phe Arg Asn Gln Glu He Gln Arg Wing Leu Trp Leu 340 345 350 Leu Leu Cys Gly Cys Phe Gln Ser Lys Val Pro Phe Arg Ser Arg Ser 355 360 365 Pro Ser Glu Val Arg Val Pro Ser Leu Gly Cys Arg Ser Met Gly Cys 370 375 380 Leu Gly Asn Ser Lys Thr Glu Asp Gln Arg Asn Glu Glu Lys Wing Gln 385 390 395 400 Arg Glu Wing Asn Lys Lys He Glu Lys Gln Leu Gln Lys Asp Lys Gln 405 410 415 Val Tyr Arg Ala Thr His Arg Leu Leu Leu Leu Gly Wing Gly Glu Ser 420 425 430 Gly Lys Ser Thr He Val Lys Gln Met Arg He Leu His Val Asn Gly 435 440 445 Phe Asn Gly Glu Gly Gly Glu Glu Asp Pro Gln Ala Wing Arg Ser Asn 450 455 460 Ser Asp Gly Glu Lys Wing Thr Lys Val Gln Asp He Lys Asn Asn Leu 465 470 475 480 Lys Glu Ala He Glu Thr He Val Ala Ala Ala Ser Asn Leu Val Pro 485 490 495 Pro Val Glu Leu Wing Asn Pro Glu Asn Gln Phe Arg Val Asp Tyr He 500 505 510 Leu Ser Val Met Asn Val Pro Asn Phe Asp Pro Pro Glu Phe Tyr 515 520 525 Glu His Ala Lys Ala Leu Trp Glu A = p Glu Gly Val Arg Ala Cys Tyr 530 535 540 Glu Arg Ser Asn Glu Tyr Gln Leu He Asp Cys Ala Gln Tyr Phe Leu 545 550 555 560 Asp Lys He Asp Val He Lys Gln Wing Asp Tyr Val Pro As Asp Gln 565 570 575 Asp Leu Leu Arg Cys Arg Val Leu Thr Ser Gly He Phe Glu Thr Lys 580 585 590 Phe Gln Val Asp Lys Val Asn Phe His Met Phe Asp Val Gly Gly Gln 595 600 605 Arg Asp Glu Arg Arg Lys Trp He Gln Cys Phe Asn Asp Val Thr Wing 610 615 620 He He Phe Val Val Wing Being Ser Tyr Asn Met Val He Arg Glu 625 630 635 640 Asp Asn Gln Thr Asn Arg Leu Gln Glu Wing Leu Asn Leu Phe Lys Ser 645 650 655 Ile Trp Asn Asn Arg Trp Leu Arg Thr He Ser Val He Leu Phe Leu 660 665 670 Asn Lys Gln Asp Leu Leu Wing Glu Lys Val Leu Wing Gly Lys Ser Lys 675 680 685 He Glu Asp Tyr Phe Pro Glu Phe Wing Arg Tyr Thr Thr Pro Glu Asp 690 695 700 Wing Thr Pro Glu Pro Gly Glu Asp Pro Arg Val Thr Arg Ala Lys Tyr 705 710 715 720 Phe He Arg Asp Glu Phe Leu Arg He Ser Thr Wing Ser Gly Asp Gly 725 730 735 Arg His Tyr Cys Tyr Pro His Phe Thr Cys Wing Val Asp Thr Glu Asn 740 745 750 He Arg Arg Val Phe Asn Asp Cys Arg Asp He He Gln Arg Met His 755 760 765 Leu Arg Gln Tyr Glu Leu 770 775

Claims (1)

1. CLAIMS 1. A small molecule inverse GPR6 agonist. 2. A method for modulating by reverse agonism the G protein coupled receptor, GPR6, which comprises the step of contacting GPR6 with a small molecule inverse GPR6 agonist. 3. The small molecule GPR6 inverse agonist according to claim 1 structurally represented as follows: wherein R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR15COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR1 3R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R6 and R7 are each independently selected from H, straight chain alkyl d-β, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R1 are each independently selected from H, straight chain C? -8 alkyl, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl > C2.8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl C? .8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R? 4, (CH2) mSO3H , and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl C? .8, branched alkyl, C2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH2aryl, wherein each of said aryl group or said portion of aryl of said CH2aryl group can be optionally substituted by up to four substituents at any position on said aryl, each said position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5Hn, OC6Hn, OC6H3, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OS02C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, S4 H9, SC5H9, SC5Hn, SCeHn, SC6H? 3, SCF3, SCOCH3, SCOC2H5) SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2N HC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2 , CONHC4H9, CON (C4H9) 2, and wherein when R3 and / or R14 contain an aryl ring, said aryl ring being substituted at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; or R13 and R14 can be part of a cyclic structure of 5, 6 or 7 members which can be either saturated or unsaturated and which can contain up to four heteroatoms selected from O, N, and S and said cyclic structure can be optionally substituted by up to four substituents in any position selected independently of: F, Cl, Br, I, CF3, CCI3, CH3, C2H5) C3H7, C4H9, NH2, NHCH3, N (CH3) 2 NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5 NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9 OCsHn, OCßHn, OC6H13, OCF3) OCOCH3, OCOC2H5, OCOC3H7) OCOC4H9 OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7 SC4H7, SC4H9, SC5H9, SCsHn, SCßHn, SC6H13, SCF3, SCOCH3, SCOC2H5 SCOC3H7, SCOC4H9, SO3CH3, SO3C2Hs, SO3C3H7, SO3C4H9 , SO2NH2 SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7 S02N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3 >; COOC2H5 COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2 CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2 CONHC4H9, CON (C4H9) 2, or where when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl C? s, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C9 alkylcycloalkyl and C2-8 alkenyl. The method according to claim 2, characterized in that the small molecule GPR6 inverse agonist is structurally represented as follows: wherein R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR 5COR12, NR15SO2R12 , OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R6 and R7 are each independently selected from H, straight chain alkyl d.8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, straight chain alkyl C8-8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R 12 is selected from H, branched alkyl straight chain alkyl, C 3-8 cycloalkyl, cycloalkylalkyl or C 1-9 alkylcycloalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2) n NR 13 R 14, (CH 2) m SO 3 H, and (CH 2) mCO 2 H in where n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl C? 8, branched alkyl, C2.8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH2aryl, wherein each of said aryl group or said portion of aryl of said CH2aryl group can be optionally substituted by up to four substituents at any position on said aryl, each said position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H6, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OC6Hn, OC6H13 > OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3I SC2H5l SC3H7, SC H7, SC H9, SCsH9, SC5H1 1, SCdHn, SCßH? 3) SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9 , SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and where when R13 and / or R14 contain an aryl ring, said ring of ary being substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; or R13 and R14 can be part of a cyclic structure of 5, 6 or 7 members which can be either saturated or unsaturated and which can contain up to four heteroatoms selected from O, N, and S and said cyclic structure can be optionally substituted by up to four substituents in any selected position independently of: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7 > C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9 > N (C4H9) 2, NHCOH, NHCOCH3) NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCeHn, OC6H1 3, OCF3, OCOCH3, OCOC2H5 , OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC H7, SC H9, SCsHg, SC5H1 1, SCßHn, SCßH? 3, SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, S02NHCH3, SO2N (CH3) 2, SO2NHC2H5 > SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3) COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7) COSC4H9, CONH2) CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, or where when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, branched alkyl straight chain alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2.8 alkenyl. 5. The small molecule GPR6 inverse agonist according to claim 1 structurally represented as follows: wherein R1, F2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR1 3R14, NR15COR12 , NR1 5SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR1 5 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; R8, R9, R10 and R11 are each independently selected from H, straight chain alkyl C? 8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C .9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d-β, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R? 4, (CH2) mSO3H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl d-8, branched alkyl, C2.8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH2aryl, wherein each of said aryl group or said portion of aryl of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, N HCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCeHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5Hn, SC6Hn, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON ( C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be linked by a selected chain of CHCHCHCH , CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 can be part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and in wherein each said cyclic structure can optionally be replaced by up to four substituents in any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCgHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5Hn, SC6Hn, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a CHCHCHCH chain, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, C? -8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl and C2-8 alkenyl. The method according to claim 2, characterized in that the inverse agonist of GPR6 is structurally represented as follows: wherein R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR15COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR2, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR1 5 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2 , SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; R8, R9, R10 and R11 are each independently selected from H, C1-8 straight chain alkyl, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d.8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R? 4, (CH2) mSO3H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl C? 8, branched alkyl, C2.8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH2aryl, wherein each of said aryl group or said portion of The aryl of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5 , N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3 > OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5H,? , OCßHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC H, SC H9, SCsHg, SC5H11, SCßHn, SC8H? 3, SCF3, SCOCH3 , SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3 l COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7l COSC4H9 l CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and where when R13 and / or R14 contain a substituted aryl ring in two positions adjacent to said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 can be part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and in where each said cyclic structure can optionally be replaced by up to four substituents in any position, each position selected independently of: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9 | NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCeH n, OC6H1 3, OCF3, OCOCH3, OCOC2H5 > OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC H7, SC H9, SCsHg, SC5H1 1, SCsHn, SC8H3, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5 SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2) CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7 > COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2 > CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2) and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2ICH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl C? .8, branched alkyl, C8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2.8 alkenyl. 7. The small molecule GPR6 inverse agonist according to claim 1 structurally represented as follows: where at least one of V, W, XY and Z is selected from N and each of V, W. X, Y and Z which is / are not N are independently selected from CR1, CR2, CR3, CR4 and CR5, with the provision that at least two of V, W, X, Y and Z are different from N; R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR15COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR1 3R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CN R1 5 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and at any of two adjacent positions of R1, R2, R, R and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2 SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R8, R9, R10 and R1 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d-8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C9.9 alkylcycloalkyl) C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R14, (CH2) mSO3H, and ( CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C2.8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, and CH2aryl, wherein each of said group is ryl or said portion of aryl of said CH2aryl group can be optionally substituted by up to four substituents at any position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5H,? , OCßHn, OC6H1 3, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9 > SC5H1 1, SCßHn, SC6H1 3, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each such cyclic structure can optionally be replaced by up to four substituents at any position, each position independently selected from: F, Cl, Br, I, C F3, CCI3, C H3, C2H5, C3H7, C4H9, NH2, NHCH3 > N (CH3) 2, N HC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2 l NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, N HSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCßHn, OC6H13, OCF3 > OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO 2 CH 3, OSO 2 C 2 H 5, OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 H 9, SC 6 H 9, SC 6 H 13, SCOCH 3, SCOC 2 H 5 SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4Hg) 2, and where when R13 and R14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2) CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a two-chain structure cyclical; and R15 is selected from H, C? -8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2-8 alkenyl. The method according to claim 2, characterized in that the small molecule inverse GPR6 agonist is structurally represented as follows: where at least one of V, W, XY and Z is selected from N and each of V, W. X, Y and Z which is / are not N are independently selected from CR1, CR2, CR3, CR4 and CR5, with the provision that at least two of V, W, X, Y and Z are different from N; R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR15COR12, NR1 5SO2R12, OR12 , OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3) PO (OR12) 2R12, NO2, CN, CNR15 (NR13R14 ), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any of two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2) SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R8, R9, R10 and R11 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.g alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d-8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR? 3R? 4, (CH2) mSO3H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C2.8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH2aryl, wherein each of said aryl group or said portion of The aryl of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position of: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 > NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, N HCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, N HSO2C3H7, M HSO2C4H9, OH, OCH3, OC2H5 , OC3H7) OC4H7, OC4H9, OC5H9, OCsHn, OCßHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5Hn, SCeHn , SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7) CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2 , CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents at any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, N HCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4Hg, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCeHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SCsHn, SCeHn, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2 N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, WITH HC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be attached by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl d.8 > branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2-8 alkenyl. 9. The inverse agonist of GPR6, of small molecule according to claim 1, structurally represented as follows: wherein at least one of V, W, XY and Z is selected from N and each of V, W. X, Y and Z which is / are not N are independently selected from CR1, CR2, CR3, CR4 and CR5, with the proviso that at least two of V, W, X, Y and Z are different from N; R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12 NR13R14, NR15COR12, NR15SO2R12, OR12, OCF3 , OCF2R12, OCF2CF2R12 OCOR12, OSO2R12, OPO (OR1) 2, SR12, SCF3, SCF2R12, SCF2CF2R12 SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN CNR15 (NR13R14), CNR15 (SR12 ), COOR12, COSR12, CONR13R14, and wherein any of two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a chain selected from CHCHCHCH CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R8, R9, R10 and R11 are each independently selected from H straight chain alkyl C? 8, branched alkyl, C3.8 cycloalkyl cycloalkylalkyl or C .9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R 12 is selected from H, straight chain alkyl C 8, branched alkyl C 3-8 cycloalkyl, cycloalkylalkyl or C 4-9 alkylcycloalkyl, C 2-8 alkenyl aryl, alkylaryl, (CH 2) nNR 13 R 14, (CH 2) mSO 3 H, and (CH 2) ) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C2.8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH2applo, wherein each of said aryl group or said portion of The aryl of said CH2aryl group can be optionally substituted by up to four substituents at any position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5 NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9) OC5H9 OCsHn, OCeHn, OC6H? 3, OCF3, OCOCH3, OCOC2H6, OCOC3H7, OCOC4H9 OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7 SC4H7, SC4H9, SCsHg, SC5H1 1, SCeHn, SC8H? 3, SCF3, SCOCH3, SCOC2Hs SCOC3H7, SCOC4H9, SO3CH3, SO3C2Hs, SO3C3H7, SO3C4H9, SO2NH2 SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7 SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5 COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2 CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2 CONHC4H9 , CON (C4H9) 2, and wherein when R13 and / or R14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions may be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents at any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, MHSO2C4H9, OH, OCH3, OC2H5, OC3H7 , OC4H7, OC4H9, OC5H9, OC5Hn, OC6Hn, OC6H13, OCF3) OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC H9) SCsHg, SC5H1 1 SCeHfi , SC8H? 3, SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N ( C4H9) 2, NO2, CN, COOCH3) COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, WITH HCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7 > CON (C3H7) 2, WITH HC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2ICH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl d.8 l branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or Cg alkylcycloalkyl and C2.8 alkenyl. The method according to claim 2, characterized in that said inverse agonist of GPR6, of small molecule is structurally represented as follows: where at least one of V, W, XY and Z is selected from N and each of V, W. X, Y and Z which is / are not N are independently selected from CR1, CR2, CR3, CR4 and CR5, with the provision that at least two of V, W, X, Y and Z are different from N; R1, R2, R3, R4 and R5 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR1 3R14, NR15COR12, NR 5SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR15 (NR1 3R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R8, R9, R10 and R1 i are each independently selected from H, straight chain alkyl C? 8 l branched alkyl, C3.8 cycloalkyl) cycloalkylalkyl or C4.g alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d.8 l branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or alkylcycloalkyl C-g, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R? 4, (CH2) mSO3H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C2.8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, and CH2aryl, wherein each of said group is ryl or said portion of aryl of said CH2aryl group can be optionally substituted by up to four substituents at any position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, MHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SCsHn, SC6H ", SC6H13 , SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, S O2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5) COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON ( C3H7) 2, CONHC4H9 l CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be linked by a selected chain of CHCHCHCH , CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents at any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7 , OC4H7, OC4H9, OC5H9, OCsHn, OCgHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H, SC4Hg, SCsHg, SCsH n, SCßHn, SC8H? 3, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7 > SO3C4H9, SO2N H2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOdHg, COSCH3 , COSC2H5, COSC3H7, COSC4H9, CON H2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, WITH HC4H9, CON (C4H9) 2, and where when R13 and R14 forming a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl C? .8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2.8 alkenyl. eleven . The inverse agonist of GPR6, of small molecule according to claim 1 represented structurally as follows: wherein Z is selected from NR4, O and S; W, X or Y are independently selected from N, CR1, CR2 and CR3, with the provision that when Z is O and Y is N, then W is CR1 and X is CR2. R1, R2 and R3 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR 5COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR1) 3, PO (OR12) 2R12, NO2, CN, CNR15 (NR1 3R14), CNR16 (SR12), COOR12, COSR12, CONR13R14, and wherein any two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R 4 is selected from H, straight chain alkyl C 8, branched alkyl, C 3-8 cycloalkyl, cycloalkylalkyl or C 4-9 alkylcycloalkyl C 2-8 alkenyl, aryl, alkylaryl, COR 5, CSR 5 and SO 2 R 5; R5, R6 and R7 are each independently selected from H, straight chain alkyl d.8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, C1.8 straight chain alkyl, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4.g alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d.8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R4, (CH2) mSO3H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl d.8, branched alkyl, C2.8 cycloalkyl or alkenyl, or alkylcycloalkyl, cycloalkylalkyl, or aryl and CH2aryl, wherein each of said aryl group or said portion of aryl of said CH2aryl group can be optionally substituted by up to four substituents at any position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, N HCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, N HSO2C3H7, N HSO2C4H9, OH, OCH3, OC2H5 , OC3H7, OC4H7, OC4H9, OC4H9, OC5H9, OCsHn, OCssH n, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5Hn, SCßHn, SC6H? 3, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9) SO2NH2, SO2N HCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2) CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions may be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2 , CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents at any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2 l NHCH3, N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, N HCOCH3, N HCOC2H5, NHCOC3H7 l NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCjH n, OCeHn, OC6H1 3, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2C H3, OSO2C2Hd, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5Hn, SCeHn, SC6H13, SCF3, SCOCH3, SCOC2H5 > SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2N HCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2N HC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7) COSC4H9, CONH2, CONHCH3, CON (CH3) 2, WITH HC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, WITH HC4H9, CON (C4H9) 2, and wherein when R13 and R14 form an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions may be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl d-8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-8 alkyl cycloalkyl and C2-8 alkenyl 1 2. The method according to claim 2, characterized in that said inverse agonist of GPR6 , of small molecule is represented structurally as follows: wherein Z is selected from NR4, O and S; W, X or Y are independently selected from N, CR1, CR2 and CR3, with the proviso that when Z is O and Y is N, then W is CR1 and X is CR2. R1, R2 and R3 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR15COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3 > SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR1) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and where either of two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R4 is selected from H, straight chain alkyl d-8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, COR5, CSR5 and SO2R5; R5, R6 and R7 are each independently selected from H, straight chain alkyl d-8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, straight chain alkyl d-8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, C?. 8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d-8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2-β alkenyl, aryl, alkylaryl, (CH2) nNR13R? , (CH2) mSO3H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl d.8, branched alkyl, C2.8 cycloalkyl or alkenyl, or alkylcycloalkyl, cycloalkylalkyl, or aryl and CH2aryl, wherein each of said aryl group or said portion of aryl of said CH2aryl group can be optionally substituted by up to four substituents at any position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, N HCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, N HSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCsHn, OCeHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7) SC4H7, SC4H9, SC5H9, SCsHn, SCeHn, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2Hs, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3 > CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions in said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents at any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, N HSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OCjHn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9 > SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5Hn, SC6Hn, SC6H1, SCF3, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5 , SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5 > COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2 (CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and where when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure, and R15 is selected from H, straight chain alkyl d-8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2.8 alkenyl.1 3. The inverse agonist of GPR6, of small molecule according to claim 1 represented structurally as follows: wherein Z is selected from NR4, O and S; W, X or Y are independently selected from N, CR1, CR2 and CR3, with the proviso that when Z is O and Y is N, then W is CR1 and X is CR2. R, R and R3 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR1 3R14, NR15COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and where either of two adjacent positions of R1, R2, R3, R4 and R5 can be joined by a selected chain of CHCHCHCH, CH2CH2CH2CH2 > CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH? O and OC H2CH2O to form a bi-cyclic structure; R4 is selected from H, straight chain alkyl d.8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, COR5, CSR5 and SO2R5; R5, R6 and R7 are each independently selected from H, straight chain alkyl d-8, branched alkyl, C3_8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl > C2.8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, C? .8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C .9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R1 i are each independently selected from H, straight chain alkyl C? .8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R 12 is selected from H, straight chain alkyl d 8, branched alkyl, C 3-8 cycloalkyl, cycloalkylalkyl or C 1-9 alkylcycloalkyl, C 2-8 alkenyl, aryl, alkylaryl, (CH 2) n NR 13 R 14, (CH 2) m SO 3 H, and ( CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl d.8, branched alkyl, C2.8 cycloalkyl or alkenyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl and CH2aryl, wherein each of said aryl group or said aryl portion of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position from: F, Cl, Br, I, CF3, CCI3, CH3 , C2H5, C3H7) C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C? H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7 , N HCOC4H9 I NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5Hn, OCeHn, OC6H13, OCF3, OCOC3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SCeHn, SC6Hn, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, C ONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions may be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2 , CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents in any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7 , OC4H7, OC4H9, OC5H9, OC5Hn, OCβHn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5Hn, SCeHn, SC6H13 , SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2 , CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2 > CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, C? .β straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2.8 alkenyl; The method according to claim 2, characterized in that the small molecule inverse agonist is structurally represented as follows: wherein Z is selected from NR4, O and S; W, X or Y are independently selected from N, CR1, CR2 and CR3, with the provision that when Z is O and Y is N, then W is CR1 and X is CR. R1, R2 and R3 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR1 5COR12, NR15SO2R12, OR1 2, OCF3 , OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO, 3R12, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR1 5 ( NR 3R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; R 4 is selected from H, straight chain alkyl C 8, branched alkyl, C 3-8 cycloalkyl, cycloalkylalkyl or C 9 alkylcycloalkyl, C 2-8 alkenyl, aryl, alkylaryl, COR 5, CSR 5 and SO 2 R 5; R5, R6 and R7 are each independently selected from H, straight chain alkyl C? 8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, straight chain alkyl d-s, branched alkyl, C3_8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, C?-8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2.8 alkenyl) aryl and alkylaryl; R12 is selected from H, straight chain alkyl C? .8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylamino, (CH2) nNR13R? 4, (CH2) mSO3H , and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C2.8 cycloalkyl or alkenyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl and CH2aryl, wherein each of said aryl group or said aryl portion of said CH2aryl group may be optionally substituted by up to four substituents at any independently selected position of: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9 > NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, MHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5H9, OC5Hn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H, SC4Hg, SCsHg, SC5H111 SCeHn, SCßH? 3, SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2 > SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON ( CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions in said ring of aryl, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2 l CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can be replaced or optionally by up to four substituents in any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3) C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9) N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5Hn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3 , OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5H9, SC6Hn, SC6H13, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2 , CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7 >; CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a selected chain of CHCHCHCH , CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl d.8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl and C2.8 alkenyl. 5. The small molecule GPR6 inverse agonist according to claim 1 structurally represented as follows: where Y is selected from NR4, O and S; W, X or Z are independently selected from N or CR1, CR2 or CR3, with the provision that when Y is O and Z is N, then W is CR1 and X is CR2 R1, R2 and R3 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR1 5COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR12) 3 > PO (OR12) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 (SR12), COOR12, COSR12, CONR13R14, and wherein any of two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2 , SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; R4 is H, straight chain alkyl d.8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or alkylcycloalkyl C4.g, C2.8 alkenyl, aryl, alkylaryl, COR5, CSR5 and SO2R5; R5, R6 and R7 are each independently selected from H, straight chain alkyl C? 8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4.g alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, straight chain alkyl d.8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or alkylcycloalkyl C. , C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R111 are each independently selected from H, straight chain alkyl d.8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d-8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R14, (CH2) mSO3H, and ( CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R 3 and R 14 are each independently selected from H, C, -8 straight chain alkyl, branched alkyl, C 2-8 cycloalkyl or alkenyl, or alkyl cycloalkyl, cycloalkylalkyl, or aryl and CH 2 aryl, wherein each of said aryl group or said aryl portion of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position of: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7 , OC4H7, OC4H9, OC5H9, OC5Hn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5Hn, SC6Hn, SC6H13 , SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2 NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON ( C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions can be linked by a selected chain of CHCHCHCH , CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents in any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9) NH2, NHCH3, N (CH3) 2 , N HC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5H1 1, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9 l SCsHg, SCgHn, SCßHn, SCeH? 3, SCF3, SCOCH3, SCOC2Hs, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2 , CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl d.8 > branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C .9 alkylcycloalkyl and C2-8 alkenyl; The method according to claim 2, characterized in that the small molecule inverse GPR6 agonist is structurally represented as follows: wherein Y is selected from NR4, O and S; W, X or Z are independently selected from N or CR1, CR2 or CR3, with the provision that when Y is O and Z is N, then W is CR1 and X is CR2. R1, R2 and R3 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR15COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2NR13R14, PO (OR1) 3, PO (OR12) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 (SR12) ), COOR12, COSR12, CONR13R14, and wherein any two adjacent positions of R1, R2, R3, R4 and Rs can be linked by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCHO or OCH2CH2O to form a bi-cyclic structure; R4 is H, straight chain alkyl C? -8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, COR5, CSR5 and SO2R5; R5, R6 and R7 are each independently selected from H, straight chain alkyl d.8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, straight chain alkyl d-8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or alkylcycloalkyl C4.g, C2-8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d-8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2-8 alkenyl, aryl, alkylaryl, (CH2) nNR13R? 4, (CH2) mSO3H, and (CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C2.8 cycloalkyl or alkenyl, or alkylcycloalkyl, cycloalkylalkyl, or aryl and CH2aryl, wherein each of said aryl group or said aryl portion of said CH2aryl group may be optionally substituted by up to four substituents at any independently selected position from: F, Cl, Br, I, CF3, CCI3, CH3) C2H5, C3H7, C4H9, NH2, NHCH3 l N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2 l NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7 , OC4H7, OC4H9, OC5H9, OC5Hn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5Hg, SC5Hn, SC6Hn, SC6H3, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2 , CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain an aryl ring substituted at two adjacent positions on said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents in any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , NHC2H5) N (C2HS) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7? NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5H9, OC5Hn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7) SC4H7, SC4Hg, SCsHg, SCsHn, SCßHn, SCeH? 3 > SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be linked by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2) CH2CH2CH2, CH2CH2 , SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, straight chain alkyl d-8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl and C2-8 alkenyl. 17. The small molecule GPR6 inverse agonist according to claim 1 structurally represented as follows: where Y is selected from NR4, O and S; W, X or Z are independently selected from N or CR1, CR2 or CR3, with the provision that when Y is O and Z is N, then W is CR1 and X is CR2 R1, R2 and R3 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR15COR12, NR15SO2R12, OR12, OCF3, OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R12, SO2N R13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CN R1 5 (NR1 3R14), CNR1 5 (SR12), COOR12, COSR12, CONR13R14, and 1 2 wherein any two adjacent positions of R, R, R3, R4 and R5 can be linked by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; R4 is selected from H, straight chain alkyl d-8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, COR5, CSR5 and SO2R5; R5, R6 and R7 are each independently selected from H, straight chain alkyl C? .8, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or Cg alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, straight chain alkyl d.3, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2.8 alkenyl, aryl and alkylaryl; R12 is selected from H, C1-8 straight chain alkyl, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R14, (CH2) mSO3H, and ( CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, straight chain alkyl d.8, branched alkyl, C2.8 cycloalkyl or alkenyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl and CH2aryl, wherein each of said aryl group or said Aryl portion of said CH2aryl group can be optionally substituted by up to four substituents at any independently selected position from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7 , OC4H7, OC4H9, OC5H9, OCsHn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3) SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5Hn, SC6Hn, SC6H13 , SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7 ) 2) SO2NHC4H9 > SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and / or R14 contain a substituted aryl ring at two adjacent positions on said aryl ring, then said two adjacent positions may be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2 , CHCHCH2 > CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents in any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9 >; N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7l OC4H9, OC5H9) OC5Hn, OC6Hn, OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7 , OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC H, SC4Hg, SCsHg, SC5H11, SCßHn, SCeH-? 3 SCF 3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7 , SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3 , COSC2H5, COSC3H7 > COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring in two adjacent positions in said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; and R 5 is selected from H, straight chain alkyl d-8, branched alkyl, C 3-8 cycloalkyl, cycloalkylalkyl or C 4-9 alkylcycloalkyl and C 8 alkenyl. 18. The method according to claim 2, characterized in that the inverse agonist of GPR6, of small molecule is structurally represented as follows: where Y is selected from NR4, O and S; W, X or Z are independently selected from N or CR1, CR2 or CR3, with the provision that when Y is O and Z is N, then W is CR1 and X is CR2. R1, R2 and R3 are each independently selected from the following: H, F, Cl, Br, I, R12, CF3, CF2R12, CF2CF2, CCI3, CCI2R12, CCI2CCI2R12, NR13R14, NR15COR12, NR15SO2R12, OR12, OCF3) OCF2R12, OCF2CF2R12, OCOR12, OSO2R12, OPO (OR12) 2, SR12, SCF3, SCF2R12, SCF2CF2R12, SCOR12, SO3R1 2, SO2NR13R14, PO (OR12) 3, PO (OR12) 2R12, NO2, CN, CNR15 (NR13R14), CNR15 ( SR12), COOR12, COSR12, CONR13R14, and wherein any of two adjacent positions of R1, R2, R3, R4 and R5 can be linked by a selected chain of CHCHCHCH, CH2CH2CH2CH2, CHCHCH2) CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; R4 is selected from H, straight chain alkyl d.8, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloaicyl, C2-8 alkenyl, aryl, alkylaryl, COR5, CSR5 and SO2R5; R5, R6 and R7 are each independently selected from H, straight chain alkyl d-β, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R6 and R7 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4-9 alkylcycloalkyl, C2-8 alkenyl, aryl and alkylaryl; R8, R9, R10 and R11 are each independently selected from H, straight chain C? -8 alkyl, branched alkyl, C3-8 cycloalkyl, cycloalkylalkyl or C4.9 alkylcycloalkyl, C2_8 alkenyl, aryl and alkylaryl; R12 is selected from H, straight chain alkyl d.8) branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C -9 alkylcycloalkyl, C2.8 alkenyl, aryl, alkylaryl, (CH2) nNR13R14, (CH2) mSO3H, and ( CH2) mCO2H wherein n is 2 to 6 and m is 1 to 6; R13 and R14 are each independently selected from H, C? -8 straight chain alkyl, branched alkyl, C2.8 cycloalkyl or alkenyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl and CH2aryl, wherein each of said aryl group or said aryl portion of said CH2aryl group may be optionally substituted by up to four substituents at any independently selected position from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3, N (CH3) 2, NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9l N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5 > NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7, OC4H7, OC4H9, OC5H9, OC5Hn, OC6Hn, OC6H13, OCF3, OCOC3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7 > OSO2C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4H9, SC5H9, SC5H9, SC6Hn, SC6H13, SCF3, SCOCH3, SCOC2H5, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, SO2NHC3H7, SO2N (C3H7) 2, SO2NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and where when R3 and / or R14 contain a substituted aryl ring in two adjacent positions in said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH, SCH2S, SCH2CH2S, OCH2O or OCH2CH2O to form a bi-cyclic structure; or R13 and R14 form part of a saturated cyclic structure of 5, 6 or 7 members or an unsaturated cyclic structure of 5, 6 or 7 members, each structure optionally containing up to four heteroatoms selected from O, N, and S and wherein each said cyclic structure can optionally be replaced by up to four substituents in any position, each position independently selected from: F, Cl, Br, I, CF3, CCI3, CH3, C2H5, C3H7, C4H9, NH2, NHCH3) N (CH3) 2 , NHC2H5, N (C2H5) 2, NHC3H7, N (C3H7) 2, NHC4H9, N (C4H9) 2, NHCOH, NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC4H9, NHSO2CH3, NHSO2C2H5, NHSO2C3H7, NHSO2C4H9, OH, OCH3, OC2H5, OC3H7 , OC4H7, OC4H9, OC5H9, OC5Hn, OC6H ", OC6H13, OCF3, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OSO2CH3, OSO2C2H5, OSO2C3H7, OS02C4H9, SH, SCH3, SC2H5, SC3H7, SC4H7, SC4Hg, SCsHg, SC5H11, SCßHn, SCeH3, SCF3, SCOCH3, SCOC2He, SCOC3H7, SCOC4H9, SO3CH3, SO3C2H5, SO3C3H7, SO3C4H9, SO2NH2, SO2NHCH3, SO2N (CH3) 2, SO2NHC2H5, SO2N (C2H5) 2, S02NHC3H7, SO2N (C3H7) 2, S02NHC4H9, SO2N (C4H9) 2, NO2, CN, COOCH3, COOC2H5, COOC3H7, COOC4H9, COSCH3, COSC2H5, COSC3H7, COSC4H9, CONH2, CONHCH3, CON (CH3) 2, CONHC2H5, CON (C2H5) 2, CONHC3H7, CON (C3H7) 2, CONHC4H9, CON (C4H9) 2, and wherein when R13 and R14 form a substituted aryl ring at two adjacent positions in said aryl ring, then said two adjacent positions can be joined by a chain selected from CHCHCHCH, CH2CH2CH2CH2, CHCHCH2, CH2CH2CH2, CH2CH2, SCH2S, SCH2CH2S, OCH2O and OCH2CH2O to form a bi-cyclic structure; and R15 is selected from H, C?. 8 straight chain alkyl, branched alkyl, C3.8 cycloalkyl, cycloalkylalkyl or C .9 alkylcycloalkyl and C2.8 alkenyl. 19. A small molecule GPR6 inverse agonist selected from the group consisting of the following structures: ARE1.11 ARE112 ARE1U5 ARE116 ARE117 ARE118 ARE119 ARE120 ARE121 ARE122 ARE123 ARE124 ARE125 ARE126 AR1Í129 ARE130 ARE133 ARE134 ARE135 ARE136 ARE139 ARE140 ARE141 ARE142 ARE143 ARE144 ARE149 ARE150 ARE151 ARE152 ARE1S3 ARE154 ARE15S ARE 156 20. A method for modulating by reverse agonism the G protein coupled receptor, GPR6, comprising the step of contacting GPR6 with a small molecule inverse GPR6 agonist selected from the group consisting of: ARE111 ARE112 ARE115 ARE116 ARE117 ARE118 ARE119 ARE120 ARE121 ARE122 ARE123 ARE124 ARE125 ARE126 ARE129 ARE130 ARE131 ARE132 AREl.33 ARE134 ARE135 ARE136 ARE 139 ARE140 ARE141 ARE142 ARE143 ARE144 AREI49 ARE150 ARE151 ARE152 ARE153 ARE154 ARE155 ARE156