EP0946595A2 - Melanocortinderivate, die spezifisch an melanocortinrezeptoren des typs 3, 4 oder 5 binden - Google Patents

Melanocortinderivate, die spezifisch an melanocortinrezeptoren des typs 3, 4 oder 5 binden

Info

Publication number
EP0946595A2
EP0946595A2 EP97950498A EP97950498A EP0946595A2 EP 0946595 A2 EP0946595 A2 EP 0946595A2 EP 97950498 A EP97950498 A EP 97950498A EP 97950498 A EP97950498 A EP 97950498A EP 0946595 A2 EP0946595 A2 EP 0946595A2
Authority
EP
European Patent Office
Prior art keywords
msh
peptides
peptide
receptors
ala
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97950498A
Other languages
English (en)
French (fr)
Inventor
Roger Antonius Hendricus Adan
Johannes Peter Henri Burbach
Willem Hendrik Gispen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Quadrant Holdings Cambridge Ltd
Original Assignee
Quadrant Holdings Cambridge Ltd
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 Quadrant Holdings Cambridge Ltd filed Critical Quadrant Holdings Cambridge Ltd
Priority to EP97950498A priority Critical patent/EP0946595A2/de
Publication of EP0946595A2 publication Critical patent/EP0946595A2/de
Withdrawn legal-status Critical Current

Links

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
    • C07K14/68—Melanocyte-stimulating hormone [MSH]
    • C07K14/685—Alpha-melanotropin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • 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 relates to the field of melanocortin peptides .
  • Melanocortins (which used to be called me1anotropines also) are peptides originally derived from a larger precursor protein named pro-opiomelanocortin.
  • the natural melanocortins share the heptapeptide core sequence Met-Glu-His-Phe-Arg-Trp- Gly.
  • These melanocortins include ⁇ -MSH ( ⁇ -melanocyte stimulating hormone), ⁇ -MSH, ⁇ -MSH, ⁇ -LPH ( ⁇ -lipotropin hormone) and ACTH ( adrenocorticotrope hormone) .
  • Melanocortins have a wide range of biological activities.
  • MCR-1 Melanocortin receptor 1
  • MCR-2 is the ACTH receptor expressed in for instance the adrenal gland.
  • the invention provides a peptide having specific binding affinity for a melanocortine receptor, preferably the mc3, mc4 or mc5 receptor comprising the sequence
  • X and Y are amino acid residues and Z is an aromatic amino acid residue.
  • the above peptides are agonists for MSH activity which are highly potent.
  • a very important contribution to the high potency can be attributed to the 7-position (counted as in the original ACTH-molecule) which should be D-2-thienyl-Ala or 3-pyridyl-D-Ala and for which only very limited and very similar residues may be substituted without losing the increase in agonist potency.
  • Another important contribution to MSH agonistic activity is the omission of residues 1-3 and/or the omission of residues 11-13.
  • a high contribution to activity is also provided by the presence of an aromatic amino acid residue at position 9.
  • Positions 4 and 5 should normally not be omitted; these residues should be present though it is far less critical which amino acid residues are present at said positions. It is clear that at least conserved substitutions are allowed for these positions, but also less conserved substitutions will histidine residue at position 6 and the arginine residue at position 8 are quite important for activity and should only be replaced by very conservative substitutions, if at all. Especially the more important residues in general should not be all replaced by substitutes in one and the same molecule.
  • the preferred residue at position is Naftyl-alanine, be it- in the D-or in the L-configuration. The presence of this residue leads to a further increase in potency.
  • amino acid residue at position 10 is not essential for the activity of the molecule, but it does seem to have some effect. If a residue is present it is preferred that this residue is glycine or lysine, whereby the latter has the additional advantage that it provides a reactive moiety which can be used to couple the peptide to other molecules or to make the peptide cyclic. In the event that a cyclic peptide is to be produced, which is preferred, since the half-life of such a cyclic peptide is improved over the half-life of the linear form, then a reactive moiety at the other end should also be provided.
  • Cyclic peptides can however also be produced by providing reactive moieties outside the essential core that enable closure of the loop, such as reactive moieties leading to a lactam.
  • the preferred residues at positions X and Y are Nle for X and Gly or Asp for Y, whereby the presence of Asp leads to a further advantage in having a reactive moiety for making a lactam.
  • the peptides according to the invention are generally more potent than MSH itself.
  • the preferred peptides have potencies of up to 100 times the potency of MSH. Less potent peptides are within the scope of the present invention, since potency is not the only criterion which is required for a successful peptide-based drug.
  • half-life and selectivity are also important parameters. the regular in vitro tests as well as an in vivo test in rats whereby the grooming behaviour is measured.
  • the results in a grooming assay are good indications that the peptides will be able to activate the receptor and thereby the G-protein cascade coupled to said receptor and thus the peptides can be used as agonists for MC-receptors .
  • Targeting the MC-receptor in particular of the MC-4 receptor for which a particularly selective peptide has been provided by the present invention in an agonistic manner is useful in the treatment of CNS- disorders, neurophathies , obesity, and in particular for diabetes related neuropathy, as well as neuropathy as a result of cytotoxic treatments (chemotherapy and the like).
  • the present invention also provides pharmaceutical compositions capable of treating the above conditions. Dosages for such treatments will usually be given once a day in doses of about 1 ⁇ q to about 100 mg per dosage unit, preferably 10 ⁇ q - 10 mg, more preferably 50 ⁇ q - 1 mg. The dosage should result in a concentration in the body of between 0,1 nm and 1 ⁇ m, preferably 1 nM - 100 nM, most preferably 10 - 50 nM.
  • the compositions may comprise the usual additives for usual dosage formats for peptide drugs or for peptide derived drugs. The format is preferably an oral formulation such as a tablet, a granulate, a powder or a liquid formulation, although enteral and parenteral administrations may find application as well. Particularly preferred are compositions wherein a peptide according to the invention is combined with a drug aiming to prevent or that leads to neuropathy, such as insulin and cytotoxic agents.
  • HEK 293 Human embryonal kidney (HEK 293) cells were stably transfected with the human MC3(Gantz et al. JBC 1993. 268:8246-8250), human MC4 (Gantz et al. 1993. JBC 268:15174015179) or human MC5 receptor constructs using the calcium phosphate precipitation method.
  • a reporter plasmid 10 ⁇ g of the pCRE- LacZ vector (Chen et al. 1995. Anal.Biochem. 226:349-354), in which a cAMP responsive element drives expression of the LacZ gene, was transfected at the beginning of each experiment. The day after pCRE-LacZ transfection, cells were split in 96-wells plates. After 48 hours cells were stimulated with varying concentrations of the MC receptor ligands in assay medium
  • DMEM + 0.1 mg/ml BSA, 0.1 mM IBMX DMEM + 0.1 mg/ml BSA, 0.1 mM IBMX
  • lysis buffer 60mM sodium phosphate, 1 mM MgCl2, 5 mM ⁇ -mercaptoethanol,
  • Rats Male Wistar rats weighing 120-130 g were implanted with cannulas into the foramen intraventriculare under hypnorm anaesthesia (Brakkee et al . , Life Science vol. 17 1979, ). Rats were allowed to recover for 3 days and used for experiments during the next 10 days. In case that rats were used for more than one grooming experiment they were allowed to recover for at least 3 days between subsequent experiments. Peptides (15 ng) dissolved in 3 ⁇ g saline (154 mM NaCI) were injected i.e.v. by means of a Hamilton syringe. Grooming tests were performed according to (Gispen et al , Lab. Ani . Sci. 29 1975). Rats were placed into the observation boxes immediately after the injection. Observation started 15 min after the 15 sec over 50 min, thus the maximal grooming score for a rat is 200.
  • Preparative HPLC was carried out using a Waters Prep 4000 .
  • liquid chromatograph equipped with a Waters RCM module with two PrepPak cartridges plus quard cartridge (25x210 mm) filled with Delta-Pak C18 material.
  • Peptides were detected at 230 nm using a Waters 486 spectrophotometer with a preparative cell. Purifications were performed in gradients using water with 0.1% trifluoroacetic acid (TFA) and acetonitrile with 0.1% TFA.
  • TFA trifluoroacetic acid
  • the Hamilton Microlab 2200 was programmed to deliver washing solvents and reagents to a rack with 40 individual 4 ml columns with filter, containing Rink ( 4- ( 2 ' , 4 ' -dimethoxyphenyl-Fmoc- aminomethy1 ) -phenoxy) resin for peptide synthesis.
  • the columns were drained automatically after each step by vacuum.
  • the coupling cycle was based on Fmoc/HBTU (2-(lH-benzotriazol-l- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate) chemistry [Fields et al., Peptide Research 4, 95-101] using double coupling steps of 40 minutes. Peptides were deprotected and cleaved in 2 hrs using 1.5 ml of a mixture of trifluoroacetic acid/phenol/thioanisole/water/ethanedithiol
  • HPLC purified or crude peptides were used for cyclization via a disulfide bridge with cysteines or via a lactam bridge with the side chains of aspartic acid and lysine:
  • the peptide was dissolved in 3 ml of 40% acetic acid and purified by preparative HPLC in a gradient of 14% to 21% acetonitrile in water (containing 0.1% TFA) in 30 min. Yield after purification: 22.8 mg.
  • Lactam bridge a mixture of 20 ml of DMF (peptide grade), 26 mg of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP, 0.05 mmol) and 0.017 ml of DIEA (0.1 mmol) was added to crude MBJ07 (20 mg, 0.012 mmol). The cyclization reaction was followed by analytical HPLC. After 2 hours the mixture was acidified to pH 4 using 0.1 M HCI. The product was purified by preparative HPLC after dilution with 30 ml of water in a gradient of 21% to 30% acetonitrile in water, containing 0.1% TFA, in 30 min. Yield 15.4 mg.
  • Figure 1 shows the dose-response curves for the following peptides: MBU 23 *2GH6R7G# linear MBU 24 *2GH6R8G# linear MBU 27 *CGH6R8C# cyclic disulphate MBU 28 *2DH6R8K# cyclic lactam MBU 29 *2DH6R7K cyclic lactam
  • Figure lb Effect of the different aminoacids at position 7 and 9 together with MBU 23 and MBU 24. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors; MC3, MC4 and MC5 receptors. Values activity of 100 nM NDP-MSH.
  • FIG. 1 Effect of single aminoacid substitutions at aminoacid position number 9 of NDP-MSH.
  • the aminoacids replacing the endogenous aminoacid (Trp) are depicted. Values represent the percentage activity as compared to the maximal activity of 10 nM cc-MSH. All peptides were tested at 10 nM on HEK 293 cells stably expressing the three different MC receptors ;MC3, MC4 and MC5 receptors. At this position on an NDP-MSH background an aromatic amino acid is highly preferred.
  • Figure 3 Effect of single aminoacid substitutions at aminoacid position number 4 of Nle-MSH. On the X-axis the aminoacids replacing the endogenous aminoacid (Met) are depicted. Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors; MC3, MC4 and MC5 receptors.
  • Figure 4 Effect of single aminoacid substitutions at aminoacid position number 5 of Nle-MSH. On the X-axis the aminoacids replacing the endogenous aminoacid (Glu) are depicted. Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors; MC3, MC4 and. MC5 receptors.
  • Figure 5 Effect of single aminoacid substitutions at aminoacid position number 6 of Nle-MSH.
  • aminoacids replacing the endogenous aminoacid His
  • Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors ;MC3, MC4 and MC5 receptors. aminoacid position number 7 of Nle-MSH.
  • the aminoacids replacing the endogenous aminoacid Phe
  • Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors; MC3, MC4 and MC5 receptors.
  • Figure 7 Effect of single aminoacid substitutions at aminoacid position number 8 of Nle-MSH.
  • the aminoacids replacing the endogenous aminoacid (Arg) are depicted. Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors ;MC3, MC4 and MC5 receptors. Only five aminoacid substitutions were tested.
  • Figure 8 Effect of single aminoacid substitutions at aminoacid position number 9 of Nle-MSH.
  • the aminoacids replacing the endogenous aminoacid (Trp) are depicted. Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC-receptors ; MC3, MC4 and MC5 receptors.
  • Figure 9 Effect of single aminoacid substitutions at aminoacid position number 10 of Nle-MSH.
  • the aminoacids replacing the endogenous aminoacid (Gly) are depicted. Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors; MC3, MC4 and MC5 receptors.
  • 3 ⁇ l saline, or 3 ⁇ l saline with either 15 ng MBU peptides or 150 ng ⁇ -MSH or 1500 ng ⁇ -MSH was injected i.e.v. in rats and grooming behaviour was scored (mean ⁇ s.d.).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Endocrinology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Diabetes (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Toxicology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pyrane Compounds (AREA)
EP97950498A 1996-12-17 1997-12-17 Melanocortinderivate, die spezifisch an melanocortinrezeptoren des typs 3, 4 oder 5 binden Withdrawn EP0946595A2 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP97950498A EP0946595A2 (de) 1996-12-17 1997-12-17 Melanocortinderivate, die spezifisch an melanocortinrezeptoren des typs 3, 4 oder 5 binden

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP96203567 1996-12-17
EP96203567 1996-12-17
EP97950498A EP0946595A2 (de) 1996-12-17 1997-12-17 Melanocortinderivate, die spezifisch an melanocortinrezeptoren des typs 3, 4 oder 5 binden
PCT/NL1997/000703 WO1998027113A2 (en) 1996-12-17 1997-12-17 Melanocortin derivatives for specific binding of melanocortin receptor 3, 4 or 5

Publications (1)

Publication Number Publication Date
EP0946595A2 true EP0946595A2 (de) 1999-10-06

Family

ID=8224709

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97950498A Withdrawn EP0946595A2 (de) 1996-12-17 1997-12-17 Melanocortinderivate, die spezifisch an melanocortinrezeptoren des typs 3, 4 oder 5 binden

Country Status (6)

Country Link
EP (1) EP0946595A2 (de)
JP (1) JP2001506996A (de)
CN (1) CN1246868A (de)
AU (1) AU5348098A (de)
CA (1) CA2275442A1 (de)
WO (1) WO1998027113A2 (de)

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2338235B (en) 1997-04-15 2001-11-14 Csir Appetite suppressing plant extracts
DK1165613T3 (da) 1999-03-29 2008-08-25 Procter & Gamble Melanocortinreceptorligander
GB2396815B (en) 1999-10-27 2004-09-08 Phytopharm Plc A composition comprising a pregnenone derivative and an NSAID
WO2001030808A1 (en) * 1999-10-27 2001-05-03 The Regents Of The University Of California Methods and compounds for modulating melanocortin receptor-ligand binding
AU2001229491A1 (en) 2000-01-18 2001-07-31 Merck And Co., Inc. Cyclic peptides as potent and selective melanocortin-4 receptor antagonists
GB0012370D0 (en) * 2000-05-22 2000-07-12 Quadrant Holdings Cambridge Peptoids
GB2363985B (en) 2000-06-30 2004-09-29 Phytopharm Plc Extracts,compounds & pharmaceutical compositions having anti-diabetic activity and their use
AU2002238106A1 (en) 2001-02-13 2002-08-28 Palatin Technologies, Inc. Melanocortin metallopeptides for treatment of sexual dysfunction
AU2002322466B2 (en) 2001-07-11 2007-08-30 Palatin Technologies, Inc. Linear and cyclic melanocortin receptor-specific peptides
KR20060026011A (ko) 2003-05-09 2006-03-22 노보 노르디스크 에이/에스 비만 치료용 펩티드
EP1670815A2 (de) 2003-09-30 2006-06-21 Novo Nordisk A/S Melanocortinrezeptoragonisten
EP2033662B1 (de) 2004-01-21 2012-10-17 Novo Nordisk Health Care AG Transglutaminase vermittelte konjugation von peptiden.
KR101687037B1 (ko) 2008-06-09 2016-12-15 팔라틴 테크놀로지스 인코포레이티드 성기능 장애 치료용 멜라노코르틴 수용체-특이적 펩티드
WO2010144341A2 (en) 2009-06-08 2010-12-16 Palatin Technologies, Inc. Lactam-bridged melanocortin receptor-specific peptides
UY32690A (es) 2009-06-08 2011-01-31 Astrazeneca Ab Péptidos específicos para receptores de melanocortina
KR101726893B1 (ko) 2009-06-08 2017-04-13 팔라틴 테크놀로지스 인코포레이티드 멜라노코르틴 수용체-특이적 펩티드
JP2013511554A (ja) 2009-11-23 2013-04-04 パラティン テクノロジーズ，インコーポレイテッド メラノコルチン−１受容体特異的線状ペプチド
WO2011063366A1 (en) 2009-11-23 2011-05-26 Palatin Technologies, Inc. Melanocortin-1 receptor-specific cyclic peptides
JP2013514385A (ja) 2009-12-18 2013-04-25 ヤンセン ファーマシューティカ エヌ．ベー． エストロゲン関連受容体αモジュレーターとしての置換アミノチアゾロンインダゾール
EP2536716B1 (de) 2010-02-17 2014-05-21 Janssen Pharmaceutica, N.V. Aminothiazolone als err-alpha-modulatoren
JP2013519730A (ja) 2010-02-17 2013-05-30 ヤンセン ファーマシューティカ エヌ．ベー． エストロゲン関連受容体α変調剤としてのアミノチアゾロン
EP2539364A1 (de) 2010-02-26 2013-01-02 Novo Nordisk A/S Peptide zur behandlung von adipositas
BR112012021231A2 (pt) 2010-02-26 2015-09-08 Basf Plant Science Co Gmbh método para acentuar o rendimento em plantas, planta, construto, uso de um construto, método para a produção de uma planta transgênica, partes coletáveis de uma planta, produtos derivados de uma planta, uso de um ácido nucleíco e método para a produção de um produto
WO2011149841A1 (en) 2010-05-25 2011-12-01 Janssen Pharmaceutica Nv SUBSTITUTED THIAZOLIDINEDIONE INDAZOLES, INDOLES AND BENZOTRIAZOLES AS ESTROGEN-RELATED RECEPTOR-α MODULATORS
US9217023B2 (en) 2012-10-19 2015-12-22 Txp Pharma Gmbh Alpha- and gamma-MSH analogues
EP3838285A1 (de) 2014-04-22 2021-06-23 TXP Pharma GmbH Peptidanaloga mit verzweigten aminosäuresonde(n)
JP2020514365A (ja) 2017-03-15 2020-05-21 ノヴォ ノルディスク アー／エス メラノコルチン４受容体に結合可能な二環式化合物
WO2019219714A1 (en) 2018-05-15 2019-11-21 Novo Nordisk A/S Compounds capable of binding to melanocortin 4 receptor
WO2020053414A1 (en) 2018-09-14 2020-03-19 Novo Nordisk A/S Bicyclic compounds capable of acting as melanocortin 4 receptor agonists
US11590209B2 (en) 2020-01-21 2023-02-28 Palatin Technologies, Inc. Use of bremelanotide in patients with controlled hypertension

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022460A1 (en) * 1993-04-05 1994-10-13 University Patents, Inc. Diagnosis and treatment of erectile dysfunction

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9827113A2 *

Also Published As

Publication number Publication date
CA2275442A1 (en) 1998-06-25
AU5348098A (en) 1998-07-15
CN1246868A (zh) 2000-03-08
JP2001506996A (ja) 2001-05-29
WO1998027113A8 (en) 1999-09-02
WO1998027113A9 (en) 1999-11-04
WO1998027113A2 (en) 1998-06-25
WO1998027113A3 (en) 1998-08-06

Similar Documents

Publication Publication Date Title
EP0946595A2 (de) Melanocortinderivate, die spezifisch an melanocortinrezeptoren des typs 3, 4 oder 5 binden
Tatro Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides.
KR101232201B1 (ko) 멜라노코르틴 수용체 리간드
EP1165613B1 (de) Melanocortinrezeptor-liganden
JP2744910B2 (ja) ペプチド誘導体類
US7851590B2 (en) Y2 selective receptor agonists for therapeutic interventions
US8022035B2 (en) Y4 selective receptor agonists for therapeutic interventions
US7084111B2 (en) Melanocortin receptor templates, peptides, and use thereof
Satoh et al. Synthetic peptides derived from the fourth domain of CD4 antagonize CD4 function and inhibit T cell activation
US5614370A (en) Assay to identify human C5a antagonists and agonists
DE69225597T2 (de) Peptide mit einer lanthionin-brücke
AU2005224027B2 (en) Y2/Y4 selective receptor agonists for therapeutic interventions
CN100425282C (zh) 用于治疗性干预的y2/y4选择性受体激动剂
Katsoulis et al. Effects of galanin, its analogues and fragments on rat isolated fundus strips
DE69428292T2 (de) Rekombinanter c140-rezeptor, seine agonisten und antagonisten
EP0101929B1 (de) Diester von Polypeptiden, ihre Herstellung und Verwendung
CN102223898A (zh) 治疗肥胖的肽
CH654841A5 (de) Appetitzuegelnde tripeptide und verfahren zur herstellung derselben.
JPH0940699A (ja) ポリペプチド及びその用途
Naydenova et al. Synthesis and biological activity of small peptides as NOP and opioid receptors’ ligands: View on current developments
CN117683088A (zh) 一种具有血浆稳定性的多肽及其制备方法
Ramachandran Structural and functional interrelationships of adrenocorticotropin and the melanotropins
Hooper Walker et al.(45) Date of Patent: Oct. 7, 2003
Süli-Vargha Alkylating melanotropin fragment analogs

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19990705

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Withdrawal date: 20001220