CN101358379A - Combination therapy with serotonin reuptake inhibitors - Google Patents

Abstract

The invention relates to the use of a compound, which is a serotonin reuptake inhibitor, and another compound, which is a GABAB receptor antagonist, inverse agonist or partial agonist for the preparation of a pharmaceutical composition for the treatment of depression, anxiety disorders and other affective disorders, such as generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post traumatic stress disorder and social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse or any other disorder responsive to serotonin reuptake inhibitors.

Description

Combination therapy with serotonin reuptake inhibitors

This application is a Chinese patent application (National Application No. 03814438.7, International Application No. PCT/DK2003) filed on June 19, 2003 for an invention titled "Combined Therapy Using 5-HT Reuptake Inhibitors" /000412) divisional application.

technical field

The present invention relates to combinations of serotonin reuptake inhibitors and _GABAB receptor antagonists. Accordingly, the present invention relates to certain compounds and to compositions of compounds having serotonin reuptake inhibitory activity and _GABAB antagonistic, partial agonistic or inverse agonistic activity for use in the treatment of depression and other affective disorders. The combined serotonin reuptake inhibition and _GABAB antagonism, partial agonism or inverse agonism may be present in the same chemical entity or in two separate chemical entities.

Background technique

Selective serotonin reuptake inhibitors (hereafter referred to as SSRIs) have become the treatment of choice for depression, some forms of anxiety, and social phobia because they are less effective than traditional tricyclic antidepressants Potent and well tolerated with a favorable safety profile.

However, clinical studies of depression and anxiety disorders have shown that a considerable number, up to 30%, do not respond to SSRIs. Additionally, an often overlooked factor in antidepressant treatment is compliance, which can have a significant impact on motivating patients to remain on medication.

First, there is a delay in the therapeutic effect of SSRIs. Sometimes, symptoms can even get worse during the first few weeks of treatment. Second, sexual dysfunction is a common side effect of all SSRIs. Without addressing these issues, substantial progress in the pharmacological treatment of depression and anxiety is unlikely.

To address non-response, psychiatrists sometimes utilize reinforcement strategies. Augmentation of antidepressant therapy can be achieved by co-administration of mood stabilizers such as lithium carbonate or liothyronine or by the use of electroshock therapy.

In 1993, a boosting strategy with pindolol was described by Artigas et al. in Trends Pharmacol. Sci. 1993, 14, p262-263. Artigas's idea is based on microdialysis experiments in animal brains. In fact, subsequent neurochemical studies based on the desensitization hypothesis by Blier and colleagues showed that the delay in the therapeutic effect of antidepressants was associated with a gradual desensitization of 5-HT autoreceptors (Blier et al., J. Clin. Psycipharmacol. 1987 , 7suppl.6, 24S-35S). The focus of their hypothesis is that the action of SSRIs on the controlled-release somatoreceptor (5-HT _1A ) limits the release of 5-HT in the terminal regions and thus limits the inhibition of 5-HT uptake in those regions. This is supported by microdialysis experiments in rats showing that the increase in extracellular 5-HT induced by a single dose of SSRI was enhanced by co-administration of a 5-HT _1A autoreceptor antagonist (Invernizzi et al. BrainRes, 1992, 584, p 322-324 and Hjorth, S., J. Neurochem, 1993, 60, p 776-779).

The effect of compounds that inhibit serotonin reuptake in combination with 5-HT _1A receptor antagonists has been evaluated in several studies (Innis, RB et al., Eur. J. Pharmacol. 1987, 143, p. 1095- 204 and Gartside, SE, Br. J. Pharmacol, 1995, 115, p1064-1070, Blier, P. et al., Trends in Pharmacol. Science 1994, 15, 220). In these studies, 5-HT _1A receptor antagonists were found to abrogate the initial blockage of 5-HT neurotransmission induced by serotonin reuptake inhibitors and thus produce an immediate potentiation and therapeutic effect of 5-HT transmission quick effect.

Several patent applications have been filed involving the use of combinations of 5- _HTIA antagonists and serotonin reuptake inhibitors for the treatment of depression (see eg EP-A2-687 472 and EP-A2-714 663).

Another way to increase terminal 5-HT is to block the 5-HT _1B autoreceptor. Microdialysis experiments in rats have indeed shown that the increase in hippocampal 5-HT induced by citalopram is potentiated by GMC 2-29, an experimental 5-HT _1B receptor antagonist.

Several patent applications involving combinations of SSRIs and 5-HT _1B antagonists or partial agonists have also been filed (WO 97/28141, WO 96/03400, EPA-701819 and WO 99/13877).

Gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the brain; up to 50% of all central nerve synapses are GABA-ergic (Paredes R.G. & Agmo A., Neuroscience and Biobehavioral Reviews, vol 16 : pp 145-170 (1992)).

Norepinephrine, dopamine, and serotonin (5-HT) are all under the inhibitory control of GABA (Haefely W. Function of GABA in anxiolytic/antidepressant action, Elliott M.M., Heal DJ & Marsden CA (eds ), pp151-168, John Wiley & Sons, New York (1992)). There are two subtypes of GABA receptors, GABA _A and GABA _B , which have been extensively studied, and their effects on neuronal function and release of 5HT have been well documented.

Therefore, stimulation of GABA _A receptors with the agonist Simem can reduce 5-HT cell activity & 5-HT release in the raphe nucleus (Tao R. & Auerbach SBJ Psychopharmacology vol 14(2):pp 100-113(2000)) and GABA Blockade of _A receptors can increase firing and subsequently extracellular 5-HT levels (see below - Bikkokolin & Tao R. et al., British Journal of Pharmacology vol 119: pp 1375-1384 (1996)).

The GABA _B agonist baclofen reduces 5-HT in the suture and in the forebrain (Tao R. et al., British Journal of Pharmacology vol 119: pp1375-1384 (1996)) and when administered by itself , the GABA _B antagonist phaclofen to the suture (Abellán MT et al., Neuroreport vol 11: pp941-945 (2000); Tao R. et al., British Journal of Pharmacology vol 119: pp1375-1384 (1996)) or the forebrain (see below & Tao R. et al., British Journal of Pharmacology vol 119: pp 1375-1384 (1996)) had no effect on 5-HT levels. However, phaclofen administered centrally into the hippocampus or systemically was shown to significantly increase the effect of citalopram on extracellular 5-HT levels, as demonstrated in the findings reported here.

Contents of the invention

It has now surprisingly been found that _GABAB antagonists potentiate the effect of SSRIs on extracellular 5-HT levels.

It is therefore suggested that a combination of an SSRI and a _GABAB antagonist or a molecule with 5-HT reuptake inhibition and _GABAB antagonism has better efficacy and a more rapid onset of action than SSRI alone.

Antagonism against any GABA _B splice variant is claimed, including but not limited to GABA _BR1a and GABA _BR1B .

The present invention includes SSRI+GABA _B antagonists present in separate molecules or in the same molecule.

The present invention therefore provides:

Use of a _GABAB receptor antagonist, inverse agonist or partial agonist for the preparation of a pharmaceutical composition for use in combination with a serotonin reuptake inhibitor (SRI).

The present invention relates to compounds that are serotonin reuptake inhibitors, and another compound that is a _GABAB receptor antagonist, inverse agonist or partial agonist in the preparation for use in the treatment of depression, anxiety and other affective disorders , such as generalized anxiety disorder, panic anxiety disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, depression, Use in a pharmaceutical composition for pre-syndrome, cognitive impairment, impulse control disorder, attention deficit hyperactivity disorder, substance abuse or any other condition responsive to a serotonin reuptake inhibitor.

The present invention also relates to the use of _GABAB receptor antagonists, inverse agonists or partial agonists in the preparation of more rapidly acting pharmaceutical compositions for enhancing and/or providing the therapeutic effects of serotonin reuptake inhibitors.

In a preferred embodiment, the present invention relates to the above-mentioned use, wherein said serotonin reuptake inhibitor is for the treatment of depression, anxiety and other affective disorders, including generalized anxiety disorder, panic anxiety disorder, obsessive-compulsive disorder, Acute stress disorder, post-traumatic stress disorder or social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive impairment, impulse control disorder, ADHD , substance abuse, or any other condition responsive to SRIs.

In another embodiment, the present invention relates to

a) compounds that are serotonin reuptake inhibitors and _GABAB receptor antagonists, inverse agonists or partial agonists, or

b) Combinations of compounds that are serotonin reuptake inhibitors with compounds that are _GABAB receptor antagonists, inverse agonists or partial agonists

In preparation for the treatment of depression, anxiety and other affective disorders such as generalized anxiety disorder, panic anxiety disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as bulimia Anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive impairment, impulse control disorder, ADHD, substance abuse, or any other condition that responds to serotonin reuptake inhibitors Use in a composition or kit (kit of parts).

In two separate embodiments, the present invention relates to the combination of compounds that are serotonin reuptake inhibitors and compounds that are _GABAB receptor antagonists, inverse agonists or partial agonists in the preparation of compounds for the treatment of depression, anxiety and other affective disorders such as generalized anxiety disorder, panic anxiety disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, (a) a pharmaceutical composition for depression, premenstrual syndrome, cognitive impairment, impulse control disorder, attention deficit hyperactivity disorder, substance abuse, or any other condition responsive to a serotonin reuptake inhibitor, or (b ) purposes in the kit.

In yet another embodiment, the present invention relates to a pharmaceutical composition or kit comprising:

a) compounds that are serotonin reuptake inhibitors and _GABAB receptor antagonists, inverse agonists or partial agonists, or

b) a compound that is a serotonin reuptake inhibitor in combination with another compound that is a _GABAB receptor antagonist, inverse agonist or partial agonist,

And optionally a pharmaceutically acceptable carrier or diluent.

In two further independent embodiments, the present invention is directed to a pharmaceutical composition or kit comprising a compound that is a serotonin reuptake inhibitor and a compound that is a _GABAB receptor antagonist, inverse agonist or partial agonist. Another compound of the agent and optionally a pharmaceutically acceptable carrier or diluent.

In another embodiment, the present invention relates to a method for the treatment of depression, anxiety and other affective disorders, such as generalized anxiety disorder, panic anxiety disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive impairment, impulse control disorder, ADHD, substance abuse or reuptake of serotonin A method for any other condition responsive to an inhibitor comprising administering to a human in need thereof a therapeutically effective amount of

a) compounds that are serotonin reuptake inhibitors and _GABAB receptor antagonists, inverse agonists or partial agonists, or

b) Combination of a compound which is a serotonin reuptake inhibitor with another compound which is a _GABAB receptor antagonist, inverse agonist or partial agonist.

Whenever mentioned, the option

a) compounds that are serotonin reuptake inhibitors and _GABAB receptor antagonists, inverse agonists or partial agonists, and

b) Combinations of a compound that is a serotonin reuptake inhibitor with (another) compound that is a _GABAB receptor antagonist, inverse agonist or partial agonist each refer to a separate embodiment. Therefore, each of them is individually claimable.

Depression, anxiety and other affective disorders, including generalized anxiety disorder, panic anxiety disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as bulimia, Anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive impairment, impulse control disorder, attention deficit hyperactivity disorder, substance abuse and any other condition responsive to SIR are each referred to as separate implementations plan. Accordingly, each indication specified above is individually claimable whenever mentioned in this specification.

Whenever reference is made to the use of _GABAB receptor antagonists, inverse agonists or partial agonists and SRIs, pharmaceutical compositions, kits, methods of treatment and methods of identifying compounds for the treatment of depression, Anxiety and other affective disorders, including generalized anxiety disorder, panic anxiety disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder, and social anxiety disorder, eating disorders such as bulimia, anorexia, and obesity, phobias , depression, premenstrual syndrome, cognitive impairment, impulse control disorder, attention deficit hyperactivity disorder, substance abuse, and any other condition responsive to SIR, it refers to a separate embodiment. Accordingly, each of the indications specified above may be combined with the use of said _GABAB receptor antagonists, inverse agonists or partial agonists with SRIs, pharmaceutical compositions, kits, methods of treatment and agents identified for treatment. The methods of the compounds are claimed together independently.

In a specific embodiment, selective serotonin reuptake inhibitors are used in accordance with the invention.

In another specific embodiment, compounds selective for the _GABAB receptor are used according to the invention.

In yet another embodiment, compounds that are _GABAB receptor antagonists, inverse agonists are used according to the invention.

The pharmaceutical composition or kit of the present invention can be administered by simultaneous administration. The term "simultaneous administration" as used herein means that the _GABAB receptor antagonist, inverse agonist or partial agonist and the SRI are administered within no more than 15 minutes, such as up to 10 minutes, such as up to 5 minutes or such as up to 2 minutes time interval of dosing. The _GABAB receptor antagonist, inverse agonist or partial agonist and the SRI may be contained in "the same unit dosage form" or in "separate dosage forms". The term "same unit dosage form" as used herein refers to a dosage form comprising both an SRI and a _GABAB receptor antagonist, inverse agonist or partial agonist. The term "separate dosage forms" as used herein means that the _GABAB receptor antagonist, inverse agonist or partial agonist is contained in one dosage form and the SRI is contained in the other dosage form.

The simultaneous administration of the _GABAB receptor antagonist, inverse agonist or partial agonist and the SRI is optionally combined with the administration of supplemental doses of the _GABAB receptor antagonist, inverse agonist or partial agonist. Supplementary doses of the _GABAB receptor antagonist, inverse agonist or partial agonist may be given, for example, 1, 2, 3 or 4 times a day, whereas the SRI administered by "simultaneous administration" with the _GABAB receptor antagonist, An inverse agonist or partial agonist may be administered one or more times a day, eg once a day or eg twice a day. therefore:

A GABA _B receptor antagonist, inverse agonist, or partial agonist and SRI can be given by co-administration once daily, and a supplemental dose of the GABA _B receptor antagonist, inverse agonist, or partial agonist can be given once a day 1, 2, 3 or 4 times, such as 1, 2 or 3 times a day, such as once or twice a day, such as twice a day or as once a day, or

A GABA _B receptor antagonist, inverse agonist, or partial agonist and SRI can be given by simultaneous twice-daily dosing, and supplemental doses of the GABA _B receptor antagonist, inverse agonist, or partial Administration is 1, 2, 3 or 4 times, such as 1, 2 or 3 times a day, such as once or twice a day, such as twice a day or such as once a day.

Alternatively, the pharmaceutical compositions or kits of the invention are administered by sequential administration. The term "sequential administration" as used herein means that one or more daily doses of a _GABAB receptor antagonist, inverse agonist or partial agonist are combined with one or more daily doses of an SRI in excess of 15 minutes and less than 4 hours, such as more than 2 hours and less than 4 hours, such as more than 15 minutes and less than 2 hours, such as more than 1 hour and less than 2 hours, such as more than 30 minutes and less than 1 hour, such as more than Administered with an interval between two doses of 15 minutes and less than 30 minutes. An SRI or _GABAB receptor antagonist, inverse agonist or partial agonist may be administered first. The _GABAB receptor antagonist, inverse agonist or partial agonist is contained in separate dosage forms from the SRI, optionally in the same container or package. Typically, 1, 2, 3, 4 or 5 daily doses of the _GABAB receptor antagonist, inverse agonist or partial agonist and 1 or 2 daily doses of the SRI may be administered. therefore:

GABA _B receptor antagonist, inverse agonist or partial agonist and SRI can be given once daily, and GABA _B receptor antagonist, inverse agonist or partial agonist can be given 1, 2, 3, 4 times a day or 5 times, such as 1, 2, 3 or 4 times a day, such as 1, 2 or 3 times a day, such as once or twice a day, such as twice a day or such as once a day, or

_GABAB receptor antagonist, inverse agonist or partial agonist and SRI can be given twice daily and _GABAB receptor antagonist, inverse agonist or partial agonist can be given 1, 2, 3, 4 or 1 day 5 times, such as 1, 2, 3 or 4 times a day, such as 1, 2 or 3 times a day, such as once or twice a day, such as twice a day or once a day.

Thus, the pharmaceutical composition or kit of the invention may be adapted for simultaneous administration of the active ingredients, or it may be adapted for sequential administration of the active ingredients. When the pharmaceutical compositions or kits are adapted for simultaneous administration, the active ingredients may be contained in the same unit dosage form. When the pharmaceutical composition or kit is suitable for sequential administration, the active ingredients are contained in separate dosage forms, optionally in the same container or pack. "Active ingredient" as used herein refers to an SRI or _GABAB receptor antagonist, inverse agonist or partial agonist.

A kit (part of a kit) comprising a preparation of a _GABAB receptor antagonist, inverse agonist or partial agonist in a first unit dosage form, and an SRI in a second unit dosage form, and a preparation for containing said Container means for first and second dosage forms.

Specifically, the present invention relates to uses comprising the following combinations, and pharmaceutical compositions or kits comprising the following combinations:

CGP 55845 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, vilazodone, SRIs for loxetine, nefazodone, imipramine, femoxetine, and clomipramine;

CGP 62349 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vitamin SRIs for lazodone, nefazodone, imipramine, femoxetine, and clomipramine;

CGP 71982 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vitamin SRIs for lazodone, nefazodone, imipramine, femoxetine, and clomipramine;

CGP 76290 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vitamin SRIs for lazodone, nefazodone, imipramine, femoxetine, and clomipramine;

CGP 76291 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vitamin SRIs for lazodone, nefazodone, imipramine, femoxetine, and clomipramine;

CGP 35348 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vitamin SRIs for lazodone, nefazodone, imipramine, femoxetine, and clomipramine;

CGP 36742 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vitamin SRIs for lazodone, nefazodone, imipramine, femoxetine, and clomipramine;

CGP 46381 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vitamin SRIs for lazodone, nefazodone, imipramine, femoxetine, and clomipramine;

CGP 52432 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vitamin SRIs for lazodone, nefazodone, imipramine, femoxetine, and clomipramine;

CGP 54626 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vitamin SRIs for lazodone, nefazodone, imipramine, femoxetine, and clomipramine;

CGP 55845, CGP 62349, CGP 71982, CGP 76290, CGP 76291, CGP 35348, CGP 36742, CGP 46381, CGP 52432, and CGP 54626 in Bowery NG et al., Pharmacological Reviews 2002, 564 No. 2, 2p. 447 public.

SCH 50911 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vitamin SRIs for lazodone, nefazodone, imipramine, femoxetine, and clomipramine;

Phaclofen and selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vera SRIs for zodone, nefazodone, imipramine, femoxetine, and clomipramine;

Saclofen combined with citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vera SRIs for zodone, nefazodone, imipramine, femoxetine, and clomipramine;

2-hydroxysaclofen and selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxamide, venlafaxine, dapoxetine, duloxetine, SRIs for vilazodone, nefazodone, imipramine, femoxetine, and clomipramine;

GAS 360 is selected from citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine, vitamin SRIs for lazodone, nefazodone, imipramine, femoxetine, and clomipramine.

In a final embodiment, the invention relates to a drug identified for the treatment of depression, anxiety and other affective disorders such as generalized anxiety disorder, panic anxiety disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorders and social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive impairment, impulse control disorder, attention deficit hyperactivity disorder, substance abuse or serotonin relapse A method of ingesting a compound for any other disease to which an inhibitor is sensitive, comprising, in any order:

(a) measuring the ability of test compounds to inhibit serotonin reuptake and selecting compounds with _IC50 values below 20 nM;

(b) measuring the affinity of the test compound for the _GABAB receptor and selecting the compound,

The potency of the selected compounds on _GABAB receptors is then measured and compounds classified as receptor antagonists, inverse agonists are selected.

Preferred GABA _B ligands show an affinity below 1.5 μM, while other preferred ligands show an affinity below 1.0 μM, and other preferred ligands show an affinity below 500 nM. Compounds with an affinity below 100 nM are even more preferred.

Examples of assays for selection/detection of _GABAB antagonists, inverse agonists or partial agonists are, for example, the following:

Binding assays for detecting compounds with affinity for the GABA _B receptor are described in Karla et al., J.Med.Chem.1999, 42(11), 2053-2059; or Frydenvang et al., Chirality 1994, 6( 7), described in 583-589;

Potency assays for the detection of _GABAB receptor antagonists, partial agonists or inverse agonists are for example: Kamatchi et al., Brain Res. 1990, 506(2), 181-186; or Brauner-Osborne et al., Br. J. Pharmacol. 1999, 128(7), 1370-1374.

The invention also includes compounds identified according to this method, but not limited to these assays.

In accordance with the present invention, it has been found that the combination of _GABAB receptor antagonists or inverse agonists with serotonin reuptake inhibitors compared to administration of serotonin reuptake inhibitors alone as measured in microdialysis Co-administration of can significantly increase serotonin levels in the terminal region.

In accordance with the present invention, animal studies have shown that _GABAB receptor antagonists or inverse agonists provide a rapid onset of therapeutic action of serotonin reuptake inhibitors and potentiate the anxiolytic efficacy of serotonin reuptake inhibitors.

The use of _GABAB receptor antagonists, inverse agonists or partial agonists in combination with serotonin reuptake inhibitors can greatly reduce the amount of serotonin reuptake inhibitors needed to treat depression and other affective disorders and thus Reduce side effects caused by serotonin reuptake inhibitors. In particular, combinations of reduced doses of SRIs with _GABAB receptor antagonists, inverse agonists or partial agonists reduce the risk of SSRI-induced sexual dysfunction and sleep disturbance.

Coadministration of _GABAB receptor antagonists, inverse agonists, or partial agonists with serotonin reuptake inhibitors can also be used to treat refractory depression not adequately treated by serotonin reuptake inhibitors alone, i.e. depression. Typically, _GABAB receptor antagonists, inverse agonists, or partial agonists can be used as add-on therapy to enhance the response to SRIs in patients in whom at least 40-60% of symptom relief is not obtained within the first 6 weeks of treatment with SRIs.

Compounds that are both serotonin reuptake inhibitors and _GABAB receptor antagonists, inverse agonists, or partial agonists may have the potential to interact with serotonin reuptake in reducing side effects, rapid onset of action, and treatment of treatment-resistant patients. Uptake inhibitors have the same pharmacological advantages as combinations of _GABAB receptor antagonists, inverse agonists or partial agonists.

A number of antidepressants with serotonin reuptake inhibitory effects have been described in the literature. Any pharmacologically active compound that exerts its therapeutic effect primarily or in part via inhibition of serotonin reuptake in the CNS may benefit from potentiation with a _GABAB receptor antagonist, inverse agonist or partial agonist.

The following literature includes a number of serotonin reuptake inhibitors that would benefit from augmentation with _GABAB receptor antagonists, inverse agonists, or partial agonists: citalopram, escitalopram, fluoxetine, R- Fluoxetine, Santraline, Paroxetine, Fluvaloxamine, Venlafaxine, Norvanfarazine, Duloxetine, Dapoxetine, Vilazodone, Nefazodone, Imipramine, N-oxide imipramine, desipramine, pyrandamine, dazepineb, nefopam, benzfuralin, fenoxetine, femoxetine, clomipramine , cyanimipramine, ritoxetine, cyclamine, celoxetine, WY 27587, WY 27866, imeldine, afoxetine, indenechlorazine, tiflucarbene, viquinoline, milnacipran, baze Ruoning, YM 922, S 33005, F 98214-TA, FI 4503, A 80426, EMD 86006, NS 2389, S33005, OPC 14523, Butyl abafen, cyanodothepine, trimipramine, quinamide, sulfur Ping, amoxapine, nitroxazepine, McN 5652, McN 5707, VN 2222, L 792339, Luoxinduo, YM35992, 0177, Org6582, Org 6997, Org 6906, amitriptyline, N-oxidized amitriptyline, Nortriptyline, CL 255.663, pyrindole, indripping, LY 280253, LY285974, LY 113.821, LY 214.281, CGP 6085A, RU 25.591, napomezole, diazepam, trazodone, BMY 42.569, NS 2389, scromin, niquipiperazine, adenosylmethionine, sibutramine, desmethylsubitramine, didesmethylsubitramine, clofaxamin, vitamin Lazodone. The above compounds can be used in the form of bases or pharmaceutically acceptable acid addition salts thereof. Each of the serotonin reuptake inhibitors specified above refers to a separate embodiment. Accordingly, each of them and their use can be claimed separately.

Compounds such as citalopram, escitalopram, fluoxetine, R-fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, norvanafaxine, dulox Xetine, dapoxetine, vilazodone, nefazodone, imipramine, N-oxide imipramine, desipramine, pyrandamine, dazepinil, nefopam, benzyl Furaline, fenoxetine, femoxetine, clomipramine, cyanimipramine, ritoxetine, siclamin, ceroxetine, imeldine, subfuxetine, indenechlorazine, thiaflucarbine , viquinoline, milnacipran, bazaruoning, butamben, cyanodothepine, trimipramine, quinamide, dutiapine, amoxapine, nitroxazepine, Luoxinduo, amitinib Lin, N-oxidized amitriptyline, nortriptyline, pyrindole, indrying, napomezole, diazepam, trazodone, scromin, niquipiperazine, adenosylmethionine, Sibutramine, desmethylsubitramine, didesmethylsubitramine, chloroform, vilazodone,

N-[(1-[(6-fluoro-2-naphthyl)methyl]-4-piperidinyl)amino]carbonyl]-3-pyridinecarboxamide (WY27587),

[trans-6-(2-chlorophenyl)-1,2,3,5,6,10b-hexahydropyrrolo-(2,1-a)isoquinoline] (McN5707),

(dl-4-Exo-amino-8-chloro-benzo-(b)-bicyclo[3.3.1]nona-2-6α(10α)-diene hydrochloride) (Org 6997),

(dl)-(5α,8α,9α)-5,8,9,10-tetrahydro-5,9-methylenebenzocycloocten-8-amine hydrochloride (Org 6906),

[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridyl]ethyl]-3-isopropyl-6-(methyl Sulfonyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide (LY393558),

[4-(5,6-Dimethyl-2-benzofuryl)-piperidine] (CGP 6085),

Dimethyl-[5-(4-nitro-phenoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl]-amine (RU 25.591),

is preferred. The above compounds can be used in the form of bases or pharmaceutically acceptable acid addition salts thereof. Each serotonin reuptake inhibitor specified above refers to a separate embodiment. Accordingly, each of them and their use can be claimed separately.

Other therapeutic compounds that may benefit from augmentation with _GABAB receptor antagonists, inverse agonists, or partial agonists include compounds that elicit increased extracellular levels of 5-HT in the synaptic cleft, although they are not serotonin reuptake Inhibitors. One such compound is tianapristin.

Thus, in each of the aspects of the invention described herein, other compounds than SRIs that cause increased extracellular levels of serotonin may be used in place of SRIs.

The above list of serotonin reuptake inhibitors and other compounds that can cause an increase in extracellular levels of serotonin is not to be construed as limiting.

Particularly preferred SRIs of the invention include citalopram, escitalopram, fluoxetine, santraline, paroxetine, fluvaloxam, venlafaxine, dapoxetine, duloxetine , vilazodone, nefazodone, imipramine, femoxetine and clomipramine.

The term selective serotonin reuptake inhibitor (SSRI) refers to an inhibitor of the monoamine transporter, which has a stronger inhibitory effect on the serotonin transporter than the dopamine and norepinephrine transporters. Particularly preferred SSRIs according to the invention are citalopram, escitalopram, fluoxetine, fluvaloxam, santraline, duloxetine, vilnazodone and paroxetine.

In a specific independent embodiment, citalopram or escitalopram is used.

The following list includes a number of _GABAB antagonists, partial agonists or inverse agonists that can be used in accordance with the present invention: CGP-71982, CGP-76290, CGP-76291, CGP-35348, CGP-36742, CGP-46381, CGP -52432, CGP-54626, CGP-55845, CGP-62349, SCH 50911, GAS-360, Phaclofen, Saclofen, 2-hydroxysaclofen. Each _GABAB antagonist, partial agonist or inverse agonist specified above refers to a separate embodiment. Therefore, each of them is individually claimable.

In a preferred embodiment, the ligand for the _GABAB receptor is selected from CGP 71982, CGP76290, CGP 55845 and CGP 62349.

In specific independent embodiments, Phaclofen, 2-hydroxysaclofen or CGP-46381 is used.

Whenever mentioned, the terms "GABA _B antagonist, partial agonist or inverse agonist", "GABA _B receptor antagonist, partial agonist or inverse agonist", "GABA _B ligand", and " Each of "a ligand for the _GABAB receptor" refers to a _GABAB receptor antagonist, a partial _GABAB receptor agonist, and an inverse _GABAB receptor agonist. Each of these is a separate implementation. Accordingly, each of these embodiments and uses thereof are individually claimable.

Particular embodiments relate to _GABAB receptor antagonists and uses thereof.

pharmaceutical composition

Each active ingredient of the present invention can be administered alone or together or in combination with pharmaceutically acceptable carriers or excipients in the form of single or multiple doses. The pharmaceutical composition of the present invention can be used with pharmaceutically acceptable carriers or diluents and any other known adjuvants and excipients, according to conventional techniques, such as Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Those formulations disclosed in Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specially formulated for administration by any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal), the oral route is preferred. It will be appreciated that the preferred route will depend on the general condition and age of the patient being treated, the nature of the disease being treated and the particular active ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Suitably, they may be prepared with coatings such as enteric coatings or may be formulated so as to provide controlled release, eg sustained or delayed release, of the active ingredient(s) according to methods well known in the art.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups or elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions and sterile injectable solutions or dispersions which can be reconstituted before use in sterile injectable solutions or dispersions. powder. Depot injectable formulations are also contemplated as falling within the scope of this invention.

Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants and the like.

The pharmaceutical compositions of the present invention or those manufactured according to the present invention may be administered by any suitable route, for example, orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of injection solutions medication. When preparing such compositions, methods well known in the art can be used, and any pharmaceutically acceptable carriers, diluents, excipients or other auxiliary agents commonly used in the art can be used.

A typical oral dose of each active ingredient is about 0.001-about 100 mg/body weight kg/day, preferably about 0.01-about 50 mg/body weight kg/day, more preferably administered in one or more doses, such as 1-3 doses From about 0.05 to about 10 mg/kg body weight/day. The exact dosage will depend on the frequency and mode of administration, the sex, age, weight and general condition of the patient being treated, the nature and severity of the disease being treated and any concomitant disease being treated and will be apparent to those skilled in the art. other factors.

For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, the dosage will generally be about half that used for oral administration.

The compounds of the present invention can generally be used in the form of monomeric substances or pharmaceutically acceptable salts thereof. An example of this is the base addition salts of compounds that function as free acids. When the active ingredient contains a free acid, such salts are prepared by treating a free acid solution or suspension of the active ingredient with a chemical equivalent of a pharmaceutically acceptable base in a conventional manner.

For parenteral administration, solutions of one or more active ingredients in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E, or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. Said aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. Solutions for injection can be obtained by dissolving one or more active ingredients and possible adjuvants in part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling it in Prepared in suitable ampoules or vials. Any suitable adjuvants conventionally used in the art may be added, such as isotonic agents, preservatives, antioxidants and the like.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.

Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, agar, pectin, acacia, stearic acid and cellulose lower alkyl ethers, corn starch, potato starch, talc, magnesium stearate , gelatin, lactose, gum, etc.

Any other auxiliaries or additives commonly used for such purposes, such as colourings, flavorings, preservatives, etc., may be used provided they are compatible with the active ingredient used.

Examples of liquid carriers are syrup, sesame oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyethylene oxide and water. Likewise, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

Pharmaceutical compositions formed by admixing one or more active ingredients of this invention with a pharmaceutically acceptable carrier can then be readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

The active ingredients of the present invention may be formulated in similar or different pharmaceutical compositions and unit forms thereof.

If a solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatine capsule in powder or granule form, or it may be in the form of a troche or lozenge.

The amount of solid carrier used can vary widely, but will generally be from about 25 mg to about 1 g.

If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.

The pharmaceutical composition of the present invention may contain, if desired, one or more active ingredients together with pharmacologically acceptable active substances, such as those previously described.

Description of drawings

Figure 1. Effect of topical administration of bicokolin (50 μΜ) followed by systemic administration of citalopram 10 μmol/kgs.c.

Figure 2. Effect of topical administration of phaclofen (50 μM) followed by systemic administration of citalopram 10 μmol/kgs.c.

Figure 3. Effect of coadministration of phaclogen (2 mg/kg s.c.) followed by systemic administration of citalopram (10 μmol/kg s.c.).

Figure 4. Effect of administration of the GABA _B antagonist 2-hydroxysaclofen (2 mg/kg sc) on citalopram-induced increase in 5-HT levels in the anterior hippocampus of rats. F(1,172)=3.01, P<0.05 citalopram 10 μmol/kg sc, n=13, citalopram 10 μmol/kg sc and 2-hydroxysaclofen 2 mg/kg scn=3.

Figure 5. Effect of administration of GABA _B antagonist CGP 46381 (mg/kg sc) on citalopram-induced increase in 5-HT levels in rat anterior hippocampus; citalopram 10 μmol/kg sc, n=13, Citalopram 10 μmol/kg sc and CGP 463812 mg/kg scn=5; Citalopram 10 μmol/kg sc and CGP 46381 0.5 mg/kg scn=5; CGP 46381 10 mg/kg s.cn=2.

Figure 6. Effect of administration of the GABA _B antagonist Phaclofen (2 mg/kg sc) on citalopram-induced increase in 5-HT levels in the prefrontal cortex of rats. F(1,198)=3.25, P<0.05. Citalopram 10 μmol/kg sc, n=13, citalopram 10 mol/kg sc and phaclofen 2 mg/kg scn=4.

Detailed ways

Materials and methods

animal

Experiments were performed using male albino mice (285-320 g; Harlan, Zeist, The Netherlands) derived from the Wistar strain. After the operation, the rats were individually housed in plastic cages (35x35x40 cm) with food and water ad libitum. Animals were maintained on a 12h light schedule (lights on at 7:00 am). The experiments were consistent with those described by Helsinki and confirmed by the Animal Care Committee of the Faculty of Mathematics and Natural Sciences of the University of Groningen.

drug

The following drugs were used: citalopram hydrobromide, 2-hydroxysaclofen, CGP46381 (Lundbeck A/S, Copenhagen, Denmark), Phaclofen, and (+)-picoclofen (Sigma, St Louis, USA).

Operation

Microdialysis of brain serotonin levels was performed with a domestically produced type I-probe made of polyacrylonitrile/sodium methanesulfonate copolymer dialysis fibers (id 220 μm, od 0.31 μm, AN69, Hospal, Italy) . Rats previously undergoing surgery were anesthetized with isoflurane (O ₂ /N ₂ O; 300/300 ml/min). Lidocaine-HCl, 10% (m/v) was used for local anesthesia. Rats were placed in a stereotaxic frame (Kopf, USA), and probes were inserted into the anterior hippocampus (anterior hippocampus, L: +4.8mm, IA: +3.7mm, V: -8.0mm) and the middle frontal In the anterior cortex of the lobe (PFC, L-0.9 mm; AP: +3.5 mm relative to the bregma; V: -6.0 mm (Paxinos and Watson, 1982). After insertion, the probe was fixed with dental cement.

Microdialysis experiment

Rats were allowed to recover for at least 24 hours. The probe was perfused with artificial cerebrospinal fluid containing 147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl ₂ , and 1.2 mM MgCl ₂ at a flow rate of 1.5 μl/min (Harvard apparatus, South Natick, Ma., USA). The 15 min microdialysis samples were collected in HPLC vials containing 7.5 [mu]l 0.02M acetic acid for serotonin analysis.

Serotonin analysis:

A 20-μl microdialysate sample was injected via an autoinjector (CMA/200 refrigerated microsampler, CMA, Sweden) onto a 100×2.0mm C18 Hypersil 3μm column (Bester, Amstelveen, the Netherlands) and separated with mobile phase, The mobile phase was composed of 5g/L diammonium sulfate, 500mg/L EDTA, 50mg/L heptanesulfonic acid, 4% methanol v/v, and 30μl/L triethylamine, pH4.65, flow rate 0.4ml/min (Shimadzu LC -10AD). 5-HT was detected amperometrically at 500 mV vs Ag/AgCl on a glassy carbon electrode (Antec Leyden, Leiden, The Netherlands). The detection limit was 0.5 fmol 5-HT/20 μl sample (signal-to-noise ratio 3).

Data Reporting and Statistics

Four consecutive microdialysis samples with less than 20% difference were used as controls and set as 100%. Data are presented as percent of control levels (mean + S.E.M.) in time. Statistical analysis was performed using Sigmastat for Windows (SPSS, Jandel Corporation). Treatment and control pairs were compared using repeated measures analysis of variance (ANOVA) followed by the Student Newman Keuls test. The significance level was set at p<0.05.

result

Topical administration of the GABAa antagonist bicocorl, followed by systemic administration of citalopram (Figure 1)

Topical administration of 50 [mu]M bikokolin in the anterior hippocampus increased serotonin levels by approximately 150% (treatment vs. time; F(1,79)=5.20, P=0.0003). Post-hoc analysis revealed significance at t = 45-90 points.

The increase established by systemic administration of 10 μmol/kg s.c. citalopram was not affected by topical application of paeony biculine (treatment; F(1,10)=4.64, P=0.0567).

Topical administration of the GABA _B antagonist phaclofen followed by systemic administration of citalopram (Figure 2)

Local infusion of the GABA _B antagonist Phaclofen did not have any effect on 5-HT basal levels in the anterior hippocampus (F(1,9)=1.44P=0.26). Systemic administration of citalopram induced enhancement of 5-HT levels during topical administration of phaclofen (treatment F(1,9)=12.21P=0.0068, treatment vs. time F(1,112)=5.03 P<0.0001). Significant differences during the post-hoc analysis were obtained from t=75-150 points.

Simultaneous administration of phaclofen 2mg/kg s.c. and citalopram 10μmol/kg s.c. (Figure 3)

Co-administration of phaclofen 2 mg/kg s.c and citalopram 10 μmol/kg s.c. caused an increase in 5-HT levels compared with citalopram treatment alone (treatment F(1,7)=8.64P=0.021, treatment vs .Time, F(1,98)=6.38 P<0.0001). Post-hoc analysis showed different effects from t=75 to t=135.

Effect of simultaneous administration of 2-hydroxysaclofen (2 mg/kg s.c.) and citalopram 10 μmol/kg s.c. on 5-HT levels (Fig. 4)

Simultaneous administration of citalopram and the GABA _B antagonist 2-hydroxysaclofen also induces a potentiation of 5-HT levels. Treatment F(1,14)=4.80, P=0.046, treatment versus time F(1,172)=3.01, P=0.0018.

Effect of simultaneous administration of CGP 46381 and citalopram 10 μmol/kg s.c. on 5-HT levels (Fig. 5)

Administration of high doses of the GABA _B antagonist CGP 46381 (10 mg/kg sc) did not have any effect on 5-HT levels. However, an enhanced response to 5-HT levels was observed when CGP 46381 (0.5 and 2 mg/kg) was co-administered with citalopram 10 μmol/kg (0.5 mg CGP; treatment F(1,16)=4.94, p =0.04; treatment vs. time (F(1,193)=3.24,0.00081); 2mgcgp treatment F(1,16)=2.94, p=0.10; treatment vs. time (F(1,192)=3.79,0.001 ).

Effect of simultaneous administration of phaclofen 2 mg/kg s.c. and citaloprene 10 μmol/kg s.c. on 5-HT levels in PFC (Fig. 6)

Co-administration of phaclofen 2 mg/kg s.c. and citalopram 10 μmol/kg s.c. caused an increase in 5-HT levels compared with citalopram treatment alone (treatment F(1,15)=4.61P=0.048, treatment vs. .time, F(1,198)=6.3.25 P<0.0008).

Claims (7)

1. A drug identified for the treatment of affective disorders, eating disorders, phobias, dysthymia, premenstrual syndrome, cognitive impairment, impulse control disorder, attention deficit hyperactivity disorder, substance abuse, or serotonin reuptake inhibitors Any other condition responsive to the compound method, including: (a) measuring the ability of compounds to inhibit serotonin reuptake and selecting compounds with _IC50 values below 20 nM; (b) further measuring the affinity of the compounds selected from step (a) for the _GABAB receptor and selecting compounds having an affinity for the _GABAB receptor of less than 500 nM, The potency of the compounds selected from step (b) at the _GABAB receptors is then measured and compounds are selected that are antagonists, inverse agonists or partial agonists of the _GABAB receptors. 2. A drug identified for the treatment of affective disorders, eating disorders, phobias, dysthymia, premenstrual syndrome, cognitive impairment, impulse control disorder, attention deficit hyperactivity disorder, substance abuse, or serotonin reuptake inhibitors Any other condition responsive to the compound method, including: (a) measuring the affinity of the compound for the _GABAB receptor and selecting a compound having an affinity for the _GABAB receptor of less than 500 nM; (b) further measuring the ability of the compounds selected from step (a) to inhibit the reuptake of serotonin and selecting compounds with _IC50 values below 20 nM, The potency of the compounds selected from step (b) at the _GABAB receptors is then measured and compounds are selected that are antagonists, inverse agonists or partial agonists of the _GABAB receptors. 3. The method according to claim 1 or 2, wherein the affective disorder treated is selected from depression, anxiety, obsessive-compulsive disorder, acute stress disorder and post-traumatic stress disorder. 4. The method according to claim 1 or 2, wherein the affective disorder treated is selected from generalized anxiety disorder, panic anxiety disorder and social anxiety disorder. 5. The method of claim 1 or 2, wherein the eating disorder treated is selected from the group consisting of bulimia, anorexia and obesity. 6. The method of claim 1, wherein said compound has an affinity as defined in step (b) of less than 100 nM. 7. The method of claim 2, wherein said compound has an affinity as defined in step (a) of less than 100 nM.

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