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WO1996006626A1 - Procede analgesique utilisant des analogues de dynorphine tronques au niveau de la terminaison n - Google Patents

Procede analgesique utilisant des analogues de dynorphine tronques au niveau de la terminaison n Download PDF

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Publication number
WO1996006626A1
WO1996006626A1 PCT/US1994/009563 US9409563W WO9606626A1 WO 1996006626 A1 WO1996006626 A1 WO 1996006626A1 US 9409563 W US9409563 W US 9409563W WO 9606626 A1 WO9606626 A1 WO 9606626A1
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WO
WIPO (PCT)
Prior art keywords
arg
leu
lys
dynorphin
seq
Prior art date
Application number
PCT/US1994/009563
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English (en)
Inventor
Nancy M. Lee
Avram Goldstein
Original Assignee
Lee Nancy M
Avram Goldstein
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lee Nancy M, Avram Goldstein filed Critical Lee Nancy M
Priority to CZ97523A priority Critical patent/CZ52397A3/cs
Priority to JP8508677A priority patent/JPH10511077A/ja
Priority to AU76373/94A priority patent/AU7637394A/en
Priority to EP94926577A priority patent/EP0788371A1/fr
Priority to PCT/US1994/009563 priority patent/WO1996006626A1/fr
Publication of WO1996006626A1 publication Critical patent/WO1996006626A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention generally relates to dynorphin A analogues, and more particularly to dynorphin A analogues truncated at the amino terminus that are useful in analgesic methods.
  • This invention was made with government support under Grant Nos. NIDA- 02643 and NIDA-06011 awarded by the National Institutes of Health. The Government has certain rights in this invention.
  • Opioids are a large class of drugs, used clinically as painkillers, that include both plant- derived and synthetic alkaloids and peptides found endogenously in the mammalian brain. While the plant- derived alkaloids have been known and used for thousands of years, the endogenous opioid peptides were discovered only in the mid-1970s. These are known to comprise three distinct gene families: ⁇ -endorphin and other peptides derived from proopiomelanocortin; enkephalins, derived from proenkephalin A; and the dynorphins, derived from proenkephalin B.
  • Opioid compounds interact with neuronal cells and modulate physiological functions such as nociception.
  • one of the physiological effects attributed to the opioid system is analgesia.
  • Endogenous opioids exist in multiple forms in the central nervous system, and include the dynorphins, which are a series of peptides derived from the precursor prodynorphin (proenkephalin B) .
  • the first of the dynorphins to be isolated was the 17 amino acid peptide having the structure shown (and designated SEQ ID N0:1), sometimes also referred to as "dynorphin A-(l- 17)":
  • Enkephalin analogues that are conformationally constrained by a cyclic structure are described by U.S. Patent 4,518,711, issued May 21, 1985, inventors Hruby et al. Subsequently, dynorphin analogues have become known that have cysteine replacements at the amino acid residue 5 (usually leucine) and at the amino acid residue 11 (usually lysine). The amino acid residue 8 (usually an isoleucine) and the amino acid residue 13 (usually a lysine) have similarly been replaced by cysteines in a bridged relationship. The bridges, or cyclic struc ⁇ tures, appear to assist in stabilizing the dynorphin analogues against in vivo degradations.
  • Opioid drugs are used clinically as painkillers, but their usefulness is limited by the tolerance and dependence that normally develops upon chronic treatment. Tolerance may be defined as an increase in the amount of drug needed to achieve a certain level of analgesia, while dependence manifests itself in the need to continue taking drug to prevent withdrawal symptoms. Despite a great deal of research on these phenomena, little is known about their molecular basis. Opioid drugs, such as, for example, morphine, are addictive and have central opioid side effects such as drowsiness and impairment of mental activity.
  • peptides are used to relieve pain.
  • the peptides have at least six, preferably have at least seven, amino acid residues, and are analogues of dynorphin A that are truncated (with respect to endogenous dynorphin) at the N-terminus, such as being des-(Tyr), des-(Tyr-Gly) , or des-(Tyr-Gly-Gly) with respect to the endogenous dynorphin A.
  • These peptides may be formulated in a pharmaceutically acceptable solution or with a pharma- ceutically acceptable carrier, and are usefully admini ⁇ stered to a patient experiencing pain.
  • Administration of dynorphin A analogues in practicing the invention is preferably systemic, such as intravenous, and includes transnasal, transrectal, intrathecal, intramuscular, transdermal electrotran- sport, or subcutaneous procedures in dose ranges of between about 50 to about 2,000 ⁇ g/kg (or by continuous infusion). Administration may also be topical (e.g. to wounds or mucus membranes) and oral administration may also be feasible.
  • Practice of the invention is useful generally for analgesia to counter pain, and is particularly useful for painful conditions, often having unknown etiology, such as "neuropathic pain,” “neurogenic pain,” “hyperesthesia” (a morbid response to normal sensory stimuli perceived as extremely painful), “allodynia, “ “causalgia” (meaning a pathological response to nerve injury that is disabling), persistent lower back pain, visceral pain, bone pain (such as is experienced by some cancer patients), post-operative pain, and wounds such as from burns. Because practice of the invention provides non-opiate analgesia, the central nervous system side effects of a drug such as morphine (e.g. drowsiness, impaired mental functioning and the like) are avoided.
  • morphine e.g. drowsiness, impaired mental functioning and the like
  • the present invention concerns the interaction of dynorphin A analogues with non-opioid receptors in an analgesic manner.
  • preferred practice of the invention pertains to use of dynorphin A analogues that are des-(Tyr), des-(Tyr-Gly) , or des-(Tyr-Gly-Gly) with respect to dynorphin A.
  • dynorphin A-(2-17) does not bind to ⁇ , ⁇ , or K opioid receptors.
  • the non-opioid binding dynorphin A analogues show substantial antinociceptive (that is, analgesic) activity, particularly when administered systemically (such as by i.v.). This potency is retained even in morphine-tolerant animals. That is, there is a lack of cross-tolerance.
  • axons with abnormal properties are present in other conditions such as diabetic disorders.
  • syndromes of painful peripheral neuropathies are those usually classified on the basis of an associated disease, such as phantom pain when the nerve has been amputated. These types of pain are often not relieved by or are relatively resistant to opioid analgesics.
  • Peptides used in practicing the invention have at least six, and preferably have seven, amino acids.
  • suitable peptides can be viewed as having amino acid residues analogous to endogenous dynorphin A (SEQ ID N0:1), but the peptides used preferably are des-(Tyr), as shown by the amino acid residue sequences of SEQ ID NOS:4-12:
  • Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys- Trp-Asp-Asn SEQ ID N0:4
  • Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys- Trp-Asp SEQ ID N0:5
  • Trp SEQ ID NO:6
  • Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Ly s SEQ ID NO:7 ;
  • SEQ ID NO:10 Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg
  • SEQ ID NO:12 Gly-Gly-Phe-Leu-Arg-Arg-Ile
  • any one or two of the residues may be replaced with the same or a different amino acid residue in the D-configuration (to increase in vivo stability), such as where the N-terminal Gly is replaced by D-Ala, or a modification for conformational stability or rigidity may be made, such as where a plurality of the specified amino acid residues are replaced by moieties capable of forming a cyclic structure, or bridge (e.g., the disulfide bridge).
  • dynorphin A analogue is where the normal leucine at the 5 position and the lysine at the 11 position (these positions referred to as though in endogenous dynorphin), are replaced by cysteines, whose disulfide bridge provides conformational stability.
  • Any of the peptides used in practicing this invention may have the C-terminal and/or the N-terminal including a blocking group, for example, where the N-terminus has been acetylated. All the peptides can also be used in their free acid or amide form.
  • Des-(Tyr) peptides for this invention can also lack the next adjacent one or two glycine residues of the endogenous dynorphin A and thus be des-(Tyr-Gly) or des-(Tyr-Gly-Gly), as shown by SEQ ID NOS:13-21 and SEQ ID NOS:22-29, respectively, which can similarly be modified to increase conformational stability or rigidity as already described for SEQ ID NOS:4-12 and where the des-(Tyr-Gly) peptides can also have the N- terminal Gly replaced by D-Ala, the C-terminus and/or the N-terminus can include a blocking group as are well known to the art (such as to retard degradation of the peptide within the body), and the peptides can be in free acid or amide form:
  • Asp-Asn (SEQ ID N0:14); Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp- Asp (SEQ ID NO:15) ;
  • SEQ ID NOS:13-21 peptides We sometimes refer to the SEQ ID NOS:13-21 peptides as dynorphin A-(3-17) through dynorphin A-(3- 9), respectively.
  • SEQ ID NOS: 22-29 peptides we sometimes refer to the SEQ ID NOS: 22-29 peptides as dynorphin A-(4-17) through dynorphin A-(4- 10), respectively.
  • the des-(Tyr) dynorphin A-(2-17) is likewise useful in practicing this invention (SEQ ID NO: 30) with the variations and modifications known to the art and as earlier noted.
  • All the peptides suitable for practicing this invention may be readily prepared synthetically, such as by solid phase peptide synthesis techniques.
  • a chloromethylated resin or a hydroxymethyl resin has been used as a resin support, then the peptide cleaved from the resin support will be in the form of the carboxyl terminal benzyl ester, which may then be readily converted by methods well known in the art to provide the carboxyl terminal amide form of the peptide.
  • Table 1 summarizes peptides useful for analgesic, but non-opioid, properties in practicing the present invention as set out by SEQ ID NOS:22-29, and which are believed to be novel peptides. TABLE 1
  • the present invention is a new method of providing effective analgesia with completely non-opioid compounds. This means practice of the invention will avoid the addiction, tolerance, dependence, and central opioid side effects that are serious disadvantages in the use of opioid drugs.
  • Peptides of the invention are preferably formulated in a pharmaceutically acceptable solution or with a pharmaceutically acceptable carrier, and then are administered in such a solution or carrier.
  • the peptides may thus be formulated with a wide variety of physiologically acceptable carriers, such as aqueous saline and phosphate buffered saline, and may include physio ⁇ logically acceptable excipients, such as glucose, mannitol, or the like.
  • Administration may be by transdermal electrotransport (sometimes also referred to as using an iontophoretic current).
  • transdermal electrotransport sometimes also referred to as using an iontophoretic current.
  • iontophoretic current for example, such a means of drug administration is described by U.S. Patent 5,312,326, issued May 17, 1994, inventors Myers et al.
  • Other assemblies that may be suitable for selective drug release are described by U.S. Patent 5,290,240, issued March 1, 1994, inventor Horres, and by U.S. Patent 5,288,289, issued February 22, 1994, inventors Haak et al.
  • mice Randomly bred male ICR mice (Sasco, Omaha, Iowa) weighing 20 to 25 g were used in all experiments. All animals were supplied food and water ad l ibitum and were housed in a temperature (22 ⁇ 1°C)- and humidity (40-50%)- controlled animal room for at least one day before experimentation. Each mouse was used only once.
  • the abdominal stretching (writhing) assay as described by Hayashi and Takemori (1971) was used as an antinociceptive assay. Mice were injected intraperi- toneally with 10 ml/kg of 0.6% acetic acid, and the number of writhing responses per animal was counted for a six-minute period commencing five minutes after acetic acid injection. A writhe was defined as a wave of contraction of the abdominal musculature followed by a stretching of hind limbs. Number of writhes per animal was expressed as mean ⁇ S.E.
  • Antinociceptive activity was expressed as percentage decrease in the mean number of writhes observed in the drug-treated animals compared with the mean number of writhes in the saline control group. Administration of drugs was timed so that the peak action coincided with the center of the observation period. A minimum of ten mice were used at each of three dose levels to determine the dose response curve and ED 50 of the drug.
  • the data of the following Tables 2-4 use the terminology "AD 50" to indicate analgesic doses.
  • the analgesic doses represent three data points taken from at least 30 animals (and thus are the summation from dose response curves) and represent the dose at which 50% of the animals showed an analgesic effect.
  • Embodiments of the Invention ADgn (umole/kg)
  • dynorphin A- (2-17) when administered i.v. at 1.1 ⁇ mole/kg of animal weight, was an analgesic dose for 50% of the animals tested despite the animals being subjected to an injection five minutes later with acetic acid and then judged by the writhing assay.
  • Calculations show that the amounts administered of dynorphin A analogues (which are basic compounds) are insufficient to neutralize even 1% of the acidity of the administered acetic acid, and thus the effects shown from the writhing assay are not due to a simple chemical neutralization.
  • the duration of action was substantially the same when administered 30 minutes before the acetic acid, although at 60 minutes one sees the analgesic property begins to decline in duration of action.
  • the non-opioid effect of the analgesia being measured is indicated by the fact that when naloxone (50 ⁇ mole/kg) is administered in conjunction with dynorphin A-(2-17), substantially equivalent analgesic properties are still obtained.
  • Naloxone of course, is an antagonist of opioid receptors, and thus this data shows the analgesic effect is not being mediated through opioid receptors.
  • the amount of naloxone administered was more than sufficient for antagonism of opioid analgesia, both with morphine and U50,488H which act primarily at ⁇ and K opioid receptors, respectively, as shown by Table 3.
  • mice were made tolerant to morphine by implantation of a 75 mg pellet according to standard procedures, and these data show that the morphine-tolerant animals are not cross- tolerant to the des-(Tyr) dynorphin A analogue.
  • practice of the invention provides a non-opioid analgesia, where the anti- nociception is likely not an effect on the central nervous system.

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Abstract

Des analogues de dynorphine A tronqués au niveau de la terminaison N sont utilisés comme analgésiques pour soulager la douleur, telle que des neuropathies douloureuses où l'effet analgésique n'est pas opioïde. De nouveaux peptides analgésiques qui sont des-(Tyr-Gly-Gly) par rapport à la dynorphine endogène sont également décrits.
PCT/US1994/009563 1994-08-26 1994-08-26 Procede analgesique utilisant des analogues de dynorphine tronques au niveau de la terminaison n WO1996006626A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CZ97523A CZ52397A3 (en) 1994-08-26 1994-08-26 Analgesic method by dynorphin analogs being modified at n-end
JP8508677A JPH10511077A (ja) 1994-08-26 1994-08-26 Ｎ末端基で切断されたダイノルフィン類似体を用いた鎮痛方法
AU76373/94A AU7637394A (en) 1994-08-26 1994-08-26 Analgesic method with dynorphin analogues truncated at the n-terminus
EP94926577A EP0788371A1 (fr) 1994-08-26 1994-08-26 Procede analgesique utilisant des analogues de dynorphine tronques au niveau de la terminaison n
PCT/US1994/009563 WO1996006626A1 (fr) 1994-08-26 1994-08-26 Procede analgesique utilisant des analogues de dynorphine tronques au niveau de la terminaison n

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0652765A1 (fr) * 1992-06-12 1995-05-17 Des-Tyr Dynorphin Partnership Analogues de dynophine des-tyr
US5807827A (en) * 1992-06-12 1998-09-15 Des-Tyr Dynorphin Partnership Des-Tyr dynorphin analogues
US6437092B1 (en) 1998-11-06 2002-08-20 Conjuchem, Inc. Conjugates of opioids and endogenous carriers
US6566327B1 (en) 1997-10-24 2003-05-20 University Of Ottawa Histogranin peptides and their analgesic use
US6706892B1 (en) 1999-09-07 2004-03-16 Conjuchem, Inc. Pulmonary delivery for bioconjugation
US6849714B1 (en) 1999-05-17 2005-02-01 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
US6887470B1 (en) 1999-09-10 2005-05-03 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
US7112567B2 (en) 2001-02-16 2006-09-26 Conjuchem Inc. Long lasting glucagon-like peptide 2 (glp-2) for the treatment of gastrointestinal diseases and disorders
US7268113B2 (en) 2001-02-02 2007-09-11 Conjuchem Biotechnologies Inc. Long lasting growth hormone releasing factor derivatives
US7297761B2 (en) * 1996-08-08 2007-11-20 Amylin Pharmaceuticals, Inc. Pharmaceutical compositions containing exendins
US7307148B2 (en) 2004-04-23 2007-12-11 Conjuchem Biotechnologies Inc. Method for purification of albumin conjugates
WO2007053512A3 (fr) * 2005-11-01 2008-01-10 Univ Arizona State Nouveaux domaines de transduction de protéines et leurs utilisations
WO2009033799A2 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009033800A2 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
US7521423B2 (en) 1996-08-08 2009-04-21 Amylin Pharmaceuticals, Inc. Exendin pharmaceutical compositions
EP2100901A1 (fr) 1999-05-17 2009-09-16 ConjuChem Biotechnologies Inc. Insuline modifiée et ses conjugués
US7601691B2 (en) 1999-05-17 2009-10-13 Conjuchem Biotechnologies Inc. Anti-obesity agents
WO2014190313A2 (fr) 2013-05-24 2014-11-27 The Arizona Board Of Regents On Behalf Of The University Of Arizona Analogues de dynorphine a à spécificité de récepteurs de la bradykinine pour moduler une douleur neuropathique

Citations (3)

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US4361553A (en) * 1981-05-18 1982-11-30 Regents Of The University Of California Therapeutic uses of dynorphin
US4396606A (en) * 1979-11-05 1983-08-02 Addiction Research Foundation Novel polypeptide analgesics
US4462941A (en) * 1982-06-10 1984-07-31 The Regents Of The University Of California Dynorphin amide analogs

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US4396606A (en) * 1979-11-05 1983-08-02 Addiction Research Foundation Novel polypeptide analgesics
US4361553A (en) * 1981-05-18 1982-11-30 Regents Of The University Of California Therapeutic uses of dynorphin
US4462941A (en) * 1982-06-10 1984-07-31 The Regents Of The University Of California Dynorphin amide analogs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, Vol. 266, No. 1, issued 1993, TAKEMORI et al., "Suppression by Dynorphin A and ÄDesTyrÜ Dynorphin A Peptides of the Expression of Opiate Withdrawal and Tolerance in Morphine-Dependent Mice", pages 121-124. *

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0652765A4 (fr) * 1992-06-12 1997-04-09 Des Tyr Dynorphin Partnership Analogues de dynophine des-tyr.
US5807827A (en) * 1992-06-12 1998-09-15 Des-Tyr Dynorphin Partnership Des-Tyr dynorphin analogues
EP0652765A1 (fr) * 1992-06-12 1995-05-17 Des-Tyr Dynorphin Partnership Analogues de dynophine des-tyr
US7521423B2 (en) 1996-08-08 2009-04-21 Amylin Pharmaceuticals, Inc. Exendin pharmaceutical compositions
US7741269B2 (en) * 1996-08-08 2010-06-22 Amylin Pharmaceuticals, Inc. Exendins and exendin agonists for weight reduction and obesity
US7297761B2 (en) * 1996-08-08 2007-11-20 Amylin Pharmaceuticals, Inc. Pharmaceutical compositions containing exendins
US6566327B1 (en) 1997-10-24 2003-05-20 University Of Ottawa Histogranin peptides and their analgesic use
US6855692B2 (en) 1997-10-24 2005-02-15 University Of Ottawa Histogranin peptides and their analgesic use
US6500918B2 (en) 1997-11-07 2002-12-31 Conjuchem, Inc. Conjugate comprising an antinociceptive agent covalently bonded to a blood component
US6602981B2 (en) 1997-11-07 2003-08-05 Conjuchem, Inc. Antinociceptive agent derivative
US6610825B2 (en) 1997-11-07 2003-08-26 Conjuchem, Inc. Method for alleviating pain or providing an analgesic effect in a patient
US6437092B1 (en) 1998-11-06 2002-08-20 Conjuchem, Inc. Conjugates of opioids and endogenous carriers
US7906482B2 (en) 1999-05-17 2011-03-15 Advanced Diagnostics And Discovery Anti-obesity agents
US6849714B1 (en) 1999-05-17 2005-02-01 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
US7601691B2 (en) 1999-05-17 2009-10-13 Conjuchem Biotechnologies Inc. Anti-obesity agents
EP2100901A1 (fr) 1999-05-17 2009-09-16 ConjuChem Biotechnologies Inc. Insuline modifiée et ses conjugués
US6706892B1 (en) 1999-09-07 2004-03-16 Conjuchem, Inc. Pulmonary delivery for bioconjugation
US7256253B2 (en) 1999-09-10 2007-08-14 Conjuchem Biotechnologies Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
US6887470B1 (en) 1999-09-10 2005-05-03 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
US7268113B2 (en) 2001-02-02 2007-09-11 Conjuchem Biotechnologies Inc. Long lasting growth hormone releasing factor derivatives
US7737251B2 (en) 2001-02-16 2010-06-15 Conjuchem Biotechnologies Inc. Long lasting glucagon-like peptide 2 (GLP-2) for the treatment of gastrointestinal diseases and disorders
US7112567B2 (en) 2001-02-16 2006-09-26 Conjuchem Inc. Long lasting glucagon-like peptide 2 (glp-2) for the treatment of gastrointestinal diseases and disorders
US7307148B2 (en) 2004-04-23 2007-12-11 Conjuchem Biotechnologies Inc. Method for purification of albumin conjugates
WO2007053512A3 (fr) * 2005-11-01 2008-01-10 Univ Arizona State Nouveaux domaines de transduction de protéines et leurs utilisations
WO2009033800A2 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009033799A3 (fr) * 2007-09-11 2009-05-14 Mondobiotech Lab Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009033800A3 (fr) * 2007-09-11 2009-05-22 Mondobiotech Lab Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009033799A2 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2014190313A2 (fr) 2013-05-24 2014-11-27 The Arizona Board Of Regents On Behalf Of The University Of Arizona Analogues de dynorphine a à spécificité de récepteurs de la bradykinine pour moduler une douleur neuropathique
WO2014190313A3 (fr) * 2013-05-24 2015-02-05 The Arizona Board Of Regents On Behalf Of The University Of Arizona Analogues de dynorphine a à spécificité de récepteurs de la bradykinine pour moduler une douleur neuropathique
US10428115B2 (en) 2013-05-24 2019-10-01 Arizona Board Of Regents On Behalf Of The University Of Arizona Dynorphin A analogs with bradykinin receptors specificity for modulation of neuropathic pain

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EP0788371A1 (fr) 1997-08-13
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CZ52397A3 (en) 1997-07-16

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