Target Information

Target General Infomation
Target ID
T72458
Former ID
TTDC00072
Target Name
Melanocortin-4 receptor
Gene Name
MC4R
Synonyms
MC4-R; MC4R
Target Type
Clinical Trial
Disease Anorexia nervosa cachexia [ICD9: 307.1, 799.4; ICD10: F50.0-F50.1]
Cachexia [ICD9: 799.4; ICD10: R64]
Erectile dysfunction [ICD9: 302.72, 607.84; ICD10: F52.2, N48.4]
Female sexual dysfunction [ICD9: 302.7; ICD10: F52]
Metabolic disorders [ICD9: 270-279; ICD10: E70-E89]
Obesity [ICD9: 278; ICD10: E66]
Obesity; Sexual dysfunction [ICD9: 278, 302.7; ICD10: E66, F52]
Obesity; Diabetes [ICD9: 250, 278; ICD10: E08-E13, E66]
Sexual dysfunction; Obesity; Type 2 diabetes [ICD9: 250, 250.00, 250.02, 278, 302.7; ICD10: E08-E13, E11, E66, F52]
Sexual dysfunction; Obesity [ICD9: 278, 302.7; ICD10: E66, F52]
Sexual dysfunction [ICD9: 302.7; ICD10: F52]
Function
Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP).
BioChemical Class
GPCR rhodopsin
Target Validation
T72458
UniProt ID
P32245
Sequence
MVNSTHRGMHTSLHLWNRSSYRLHSNASESLGKGYSDGGCYEQLFVSPEVFVTLGVISLL
ENILVIVAIAKNKNLHSPMYFFICSLAVADMLVSVSNGSETIVITLLNSTDTDAQSFTVN
IDNVIDSVICSSLLASICSLLSIAVDRYFTIFYALQYHNIMTVKRVGIIISCIWAACTVS
GILFIIYSDSSAVIICLITMFFTMLALMASLYVHMFLMARLHIKRIAVLPGTGAIRQGAN
MKGAITLTILIGVFVVCWAPFFLHLIFYISCPQNPYCVCFMSHFNLYLILIMCNSIIDPL
IYALRSQELRKTFKEIICCYPLGGLCDLSSRY
Drugs and Mode of Action
Drug(s) Amylin Drug Info Phase 4 Discovery agent [523879], [541936]
Bremelanotide Drug Info Phase 3 Erectile dysfunction [536493]
Bremelanotide Drug Info Phase 2a Sexual dysfunction [536493]
PF-446687 Drug Info Phase 2 Female sexual dysfunction [522609]
AP-1030 Drug Info Phase 1/2 Metabolic disorders [522018], [538812]
CHIR-01020 Drug Info Preclinical Obesity [536122]
IDDBCP-150101 Drug Info Preclinical Obesity; Sexual dysfunction [536122]
MC-4 agonist Drug Info Preclinical Obesity [536122]
Melanotetan II Drug Info Preclinical Sexual dysfunction; Obesity; Type 2 diabetes [536122]
PT-15 Drug Info Preclinical Sexual dysfunction; Obesity [536122]
RM-493 Drug Info Preclinical Obesity; Diabetes [551045]
Ro-27-3225 Drug Info Preclinical Obesity [536122]
PT-14 Drug Info Discontinued in Phase 2 Erectile dysfunction [546757]
Inhibitor 1-Benzyl-4-methyl-piperazine Drug Info [527746]
1-Methyl-4-(1-phenyl-ethyl)-piperazine Drug Info [527746]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info [531079]
Ac-dR[CEHdFRWC]-NH2 Drug Info [527529]
Ac-His-D-Phe-Arg-2-Nal-NHCH3 Drug Info [528247]
Ac-His-DPhe-Arg-Trp-NH2 Drug Info [534420]
Ac-Nle-c[Asp-His-DNaI(2')-Pro-Trp-Lys]-NH2 Drug Info [530169]
Ac-Nle-c[Asp-His-DNal(2')-Pro-Trp-Lys]-NH2 Drug Info [530169]
Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2 Drug Info [530169]
AC-Nle-c[Asp-His-DPhe-Pro-Trp-Lys]-NH2 Drug Info [530169]
Ac-Phe-[Orn-Pro-cha-Trp-Arg] Drug Info [528343]
Ac-R[CEHdFRWC]-NH2 Drug Info [527529]
Ac-Tyr-D-Phe-Arg-2-Nal-NHCH3 Drug Info [528247]
Ac-YCit[CEHdFRWC]-NH2 Drug Info [527529]
Ac-YK[CEHdFRWC]-NH2 Drug Info [527529]
Ac-YRC(Me)*EHdFRWC(Me)NH2 Drug Info [527529]
Ac-YRMEHdFRWG-NH2 Drug Info [527529]
Ac-YRMEHdFRWGSPPKD-NH2 Drug Info [527529]
Ac-YR[CE(1-Me-H)dFRWC]-NH2 Drug Info [527529]
Ac-YR[CEH(d-2alpha-Nal)RWC]-NH2 Drug Info [527529]
Ac-YR[CEH(pCl-dF)RWC]-NH2 Drug Info [527529]
Ac-YR[CEH(pF-dF)RWC]-NH2 Drug Info [527529]
Ac-YR[CEHdFRWC]-NH2 Drug Info [527529]
Ac-YR[CEHdFRWC]SPPKD-NH2 Drug Info [527529]
Ac-YR[CEHFRWC]-NH2 Drug Info [527529]
Ac-[CEHdFRWC]-NH2 Drug Info [527529]
AEKKDEGPYRMEHFRWGSPPKD Drug Info [527529]
C(his-D-phe-arg-trp-Abu) Drug Info [528187]
C(his-D-phe-arg-trp-Ahp) Drug Info [528187]
C(his-D-phe-arg-trp-Ahx) Drug Info [528187]
C(his-D-phe-arg-trp-Aoc) Drug Info [528187]
C(his-L-phe-arg-trp-Aoc) Drug Info [528187]
C[CO-(CH2)2-CO-Nle-D-Nal(2)-Arg-Trp-Lys]-NH2 Drug Info [529226]
C[CO-(CH2)2-CO-Nle-D-Phe-Arg-Trp-Lys]-NH2 Drug Info [529226]
C[CO-(CH2)3-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2 Drug Info [529226]
C[CO-o-C6H4-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2 Drug Info [529226]
C[CO-o-C6H4-CO-Pro-D-Phe-Arg-Trp-Lys]-NH2 Drug Info [529226]
C[Nle-Arg-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-Asp-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-Asp-D-Phe-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-Gln-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-Glu-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-His-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-His-D-Phe-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-Nle-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-Nle-D-Phe-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-Pro-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-Pro-D-Phe-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Nle-Val-D-Phe-Arg-Trp-Glu]-NH2 Drug Info [528082]
C[Ser-Tyr-Thr-His-Dphe-Arg-Trp-Thr-Ile-Pro] Drug Info [527997]
C[Thr-Tyr-Thr-His-DNaf-Arg-Trp-Thr-Ile-Pro] Drug Info [527997]
D-Phe-Arg-2-Nal-NHCH3 Drug Info [528325]
GPYRMEHFRWGSPPKD-NH2 Drug Info [527529]
His-DPhe-Arg-Trp Drug Info [528799]
Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2 Drug Info [528343]
MCL-129 Drug Info [528626]
MK-10 Drug Info [526348]
MK-11 Drug Info [526348]
ML-253764 Drug Info [527997]
NDP-alpha-MSH Drug Info [529789]
NDP-SYSMEHFRWGKPVG Drug Info [527529]
Ser-Tyr-Ser-Nle-Glu-His-Dphe-Arg Drug Info [528799]
Tic-D-Phe-Arg-2-Nal-NHCH3 Drug Info [527941]
Agonist AMSH Drug Info [536493]
Amylin Drug Info [535068]
Bremelanotide Drug Info [536747], [536858], [536984]
CHIR-01020 Drug Info [536122]
IDDBCP-150101 Drug Info [536122]
MC-4 agonist Drug Info [536122]
Melanotetan II Drug Info [536122]
MT-II Drug Info [525923]
MTII Melanotan-II Drug Info [536493]
PT-14 Drug Info [532570]
PT-15 Drug Info [536122]
RM-493 Drug Info [551045]
Ro-27-3225 Drug Info [536122]
THIQ Drug Info [543735]
Modulator AP-1030 Drug Info [1572591]
PF-446687 Drug Info [533131]
Antagonist BL-6020 Drug Info [543735]
HS014 Drug Info [534856]
MCL0129 Drug Info [543735]
Melanocortin-4 Receptor antagonist Drug Info [536225]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Neuroactive ligand-receptor interaction
Pathway Interaction Database Syndecan-3-mediated signaling events
Reactome Peptide ligand-binding receptors
G alpha (s) signalling events
WikiPathways GPCRs, Class A Rhodopsin-like
Peptide GPCRs
GPCR ligand binding
GPCR downstream signaling
References
Ref 522018ClinicalTrials.gov (NCT00464958) One Year Extension Study To Protocol C2/5/TZ:MS-05. U.S. National Institutes of Health.
Ref 522609ClinicalTrials.gov (NCT00862888) Study to Investigate Effect of a New Drug (PF-00446687) in Males Suffering From Erectile Dysfunction. U.S. National Institutes of Health.
Ref 523879ClinicalTrials.gov (NCT01580514) Myocardial Protection of Exenatide in AMI. U.S. National Institutes of Health.
Ref 536122Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs. 2005 Aug;10(3):643-60.
Ref 536493Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007 Sep;12(17-18):757-66. Epub 2007 Aug 27.
Ref 538812(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1322).
Ref 541936(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 688).
Ref 546757Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010143)
Ref 5510452011 Pipeline of Ipsen.
Ref
Ref 525923Molecular determinants of ligand binding to the human melanocortin-4 receptor. Biochemistry. 2000 Dec 5;39(48):14900-11.
Ref 526348J Med Chem. 2002 Jun 6;45(12):2644-50.Novel cyclic templates of alpha-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527746Bioorg Med Chem Lett. 2005 Nov 15;15(22):4973-8.Privileged structure based ligands for melanocortin receptors--substituted benzylic piperazine derivatives.
Ref 527941Bioorg Med Chem Lett. 2006 Mar 15;16(6):1721-5. Epub 2005 Dec 20.Synthesis of Tic-D-Phe Psi[CH2-CH2] isostere and its use in the development of melanocortin receptor agonists.
Ref 527997J Med Chem. 2006 Feb 9;49(3):911-22.Mapping the binding site of melanocortin 4 receptor agonists: a hydrophobic pocket formed by I3.28(125), I3.32(129), and I7.42(291) is critical for receptor activation.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 528187Bioorg Med Chem Lett. 2006 Jul 15;16(14):3723-6. Epub 2006 May 5.Design of cyclic peptides with agonist activity at melanocortin receptor-4.
Ref 528247Bioorg Med Chem Lett. 2006 Sep 1;16(17):4668-73.Design and synthesis of potent and selective 1,3,4-trisubstituted-2-oxopiperazine based melanocortin-4 receptor agonists.
Ref 528325J Med Chem. 2006 Jul 27;49(15):4745-61.Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic approach.
Ref 528343Bioorg Med Chem Lett. 2006 Oct 1;16(19):5088-92. Epub 2006 Jul 28.Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivoactivity.
Ref 528626Bioorg Med Chem. 2007 Mar 1;15(5):1989-2005. Epub 2006 Dec 30.Structure-activity relationships of novel piperazines as antagonists for the melanocortin-4 receptor.
Ref 528799Bioorg Med Chem Lett. 2007 Jun 15;17(12):3310-3. Epub 2007 Apr 6.Squalene-derived flexible linkers for bioactive peptides.
Ref 529226J Med Chem. 2008 Jan 24;51(2):187-95. Epub 2007 Dec 19.Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor.
Ref 529789J Med Chem. 2008 Nov 27;51(22):7094-8.cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia.
Ref 530169J Med Chem. 2009 Jun 25;52(12):3627-35.Substitution of arginine with proline and proline derivatives in melanocyte-stimulating hormones leads to selectivity for human melanocortin 4 receptor.
Ref 531079J Med Chem. 2010 Sep 9;53(17):6386-97.Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
Ref 532570The protective effects of the melanocortin receptor (MCR) agonist, melanotan-II (MTII), against binge-like ethanol drinking are facilitated by deletion of the MC3 receptor in mice. Neuropeptides. 2014 Feb;48(1):47-51.
Ref 533131Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole. Neuropsychopharmacology. 2015 Jul;40(8):1856-65.
Ref 534420J Med Chem. 1997 Jul 4;40(14):2133-9.Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R.
Ref 534856Long-term administration of MC4 receptor antagonist HS014 causes hyperphagia and obesity in rats. Neuroreport. 1999 Mar 17;10(4):707-11.
Ref 535068Novel anti-obesity drugs. Expert Opin Investig Drugs. 2000 Jun;9(6):1317-26.
Ref 536122Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs. 2005 Aug;10(3):643-60.
Ref 536225Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs. 2006 May;11(2):315-36.
Ref 536493Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007 Sep;12(17-18):757-66. Epub 2007 Aug 27.
Ref 536747Clinical applications of centrally acting agents in male sexual dysfunction. Int J Impot Res. 2008 Jul;20 Suppl 1:S17-23.
Ref 536858Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Jun;30(5):383-408.
Ref 536984Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Oct;30(8):643-72.
Ref 543735(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 285).
Ref 5510452011 Pipeline of Ipsen.
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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