Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTD0CIQ)

• DTT Name: Melanocortin receptor 4 (MC4R)
• Synonyms: MC4-R
• Gene Name: MC4R
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: MC4R_HUMAN
• TTD ID: T72458
• Sequence:
  MVNSTHRGMHTSLHLWNRSSYRLHSNASESLGKGYSDGGCYEQLFVSPEVFVTLGVISLL
  ENILVIVAIAKNKNLHSPMYFFICSLAVADMLVSVSNGSETIVITLLNSTDTDAQSFTVN
  IDNVIDSVICSSLLASICSLLSIAVDRYFTIFYALQYHNIMTVKRVGIIISCIWAACTVS
  GILFIIYSDSSAVIICLITMFFTMLALMASLYVHMFLMARLHIKRIAVLPGTGAIRQGAN
  MKGAITLTILIGVFVVCWAPFFLHLIFYISCPQNPYCVCFMSHFNLYLILIMCNSIIDPL
  IYALRSQELRKTFKEIICCYPLGGLCDLSSRY
• Function: Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP). Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bremelanotide	DM20LIM	Hypoactive sexual desire dysfunction	HA00	Approved	[2]
Methylnaltrexone bromide	DMZTGN2	Opioid-induced constipation	DB32.1	Approved	[1]
Setmelanotide	DMPVRN9	Obesity	5B81	Approved	[3]
Amylin	DMWDEN0	N. A.	N. A.	Phase 4	[4]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AMG 386	DMQJXL4	Breast cancer	2C60-2C65	Phase 3	[1]
PF-446687	DML38VU	Female sexual arousal dysfunction	HA01.1	Phase 2	[5]
PMX-53	DMZUAJ4	Atopic dermatitis	EA80	Phase 2	[6]
AP-1030	DMBGA35	Metabolic disorder	5C50-5D2Z	Phase 1/2	[7]
PF-07258669	DM3CJ5N	Malnutrition	5B50-5B71	Phase 1	[8]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PT-14	DMYM9JL	Erectile dysfunction	HA01.1	Discontinued in Phase 2	[9]

3 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IDDBCP-150101	DMQ3BXV	Obesity	5B81	Preclinical	[1]
Melanotetan II	DMYK8MV	Obesity	5B81	Preclinical	[1]
Ro-27-3225	DMF3YQZ	Obesity	5B81	Preclinical	[1]

70 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-Benzyl-4-methyl-piperazine	DMETDQC	Discovery agent	N.A.	Investigative	[10]
1-Methyl-4-(1-phenyl-ethyl)-piperazine	DMBWSCR	Discovery agent	N.A.	Investigative	[10]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one	DMM9X0G	Discovery agent	N.A.	Investigative	[11]
Ac-dR[CEHdFRWC]-NH2	DM7XY41	Discovery agent	N.A.	Investigative	[12]
Ac-His-D-Phe-Arg-2-Nal-NHCH3	DMAQR29	Discovery agent	N.A.	Investigative	[13]
Ac-His-DPhe-Arg-Trp-NH2	DMMP0D8	Discovery agent	N.A.	Investigative	[14]
Ac-Nle-c[Asp-His-DNaI(2')-Pro-Trp-Lys]-NH2	DMLYGPW	Discovery agent	N.A.	Investigative	[15]
Ac-Nle-c[Asp-His-DNal(2')-Pro-Trp-Lys]-NH2	DMOVI7Y	Discovery agent	N.A.	Investigative	[15]
AC-Nle-c[Asp-His-DPhe-Pro-Trp-Lys]-NH2	DMG418C	Discovery agent	N.A.	Investigative	[15]
Ac-R[CEHdFRWC]-NH2	DMBFUD0	Discovery agent	N.A.	Investigative	[12]
Ac-Tyr-D-Phe-Arg-2-Nal-NHCH3	DMIH5CD	Discovery agent	N.A.	Investigative	[13]
Ac-YCit[CEHdFRWC]-NH2	DMAVPXL	Discovery agent	N.A.	Investigative	[12]
Ac-YK[CEHdFRWC]-NH2	DM5SJX8	Discovery agent	N.A.	Investigative	[12]
Ac-YRC(Me)*EHdFRWC(Me)NH2	DMWJ8UR	Discovery agent	N.A.	Investigative	[12]
Ac-YRMEHdFRWG-NH2	DMN2UKC	Discovery agent	N.A.	Investigative	[12]
Ac-YRMEHdFRWGSPPKD-NH2	DMDH5B3	Discovery agent	N.A.	Investigative	[12]
Ac-YR[CE(1-Me-H)dFRWC]-NH2	DMJK8QZ	Discovery agent	N.A.	Investigative	[12]
Ac-YR[CEH(d-2alpha-Nal)RWC]-NH2	DMVQ4KG	Discovery agent	N.A.	Investigative	[12]
Ac-YR[CEH(pCl-dF)RWC]-NH2	DM25JXM	Discovery agent	N.A.	Investigative	[12]
Ac-YR[CEH(pF-dF)RWC]-NH2	DMXCF9T	Discovery agent	N.A.	Investigative	[12]
Ac-YR[CEHdFRWC]-NH2	DMBMY73	Discovery agent	N.A.	Investigative	[12]
Ac-YR[CEHdFRWC]SPPKD-NH2	DMDO468	Discovery agent	N.A.	Investigative	[12]
Ac-YR[CEHFRWC]-NH2	DMH0EAI	Discovery agent	N.A.	Investigative	[12]
Ac-[CEHdFRWC]-NH2	DMRLOGP	Discovery agent	N.A.	Investigative	[12]
AEKKDEGPYRMEHFRWGSPPKD	DMZ8SV3	Discovery agent	N.A.	Investigative	[12]
AMSH	DMO7EBX	Female sexual arousal dysfunction	HA01.1	Investigative	[16]
BL-6020	DMQLJMC	Cachexia	MG20	Investigative	[17]
C(his-D-phe-arg-trp-Abu)	DMSLYHQ	Discovery agent	N.A.	Investigative	[18]
C(his-D-phe-arg-trp-Ahp)	DM0IJFZ	Discovery agent	N.A.	Investigative	[18]
C(his-D-phe-arg-trp-Ahx)	DMJKHAB	Discovery agent	N.A.	Investigative	[18]
C(his-D-phe-arg-trp-Aoc)	DM5NQUA	Discovery agent	N.A.	Investigative	[18]
C(his-L-phe-arg-trp-Aoc)	DMEC2PH	Discovery agent	N.A.	Investigative	[18]
C[CO-(CH2)2-CO-Nle-D-Nal(2)-Arg-Trp-Lys]-NH2	DMHARQX	Discovery agent	N.A.	Investigative	[19]
C[CO-(CH2)2-CO-Nle-D-Phe-Arg-Trp-Lys]-NH2	DMI3CSJ	Discovery agent	N.A.	Investigative	[19]
C[CO-(CH2)3-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2	DMYPHVC	Discovery agent	N.A.	Investigative	[19]
C[CO-o-C6H4-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2	DMD6OW4	Discovery agent	N.A.	Investigative	[19]
C[CO-o-C6H4-CO-Pro-D-Phe-Arg-Trp-Lys]-NH2	DMNKT8J	Discovery agent	N.A.	Investigative	[19]
C[Nle-Arg-D-Nal(2')-Arg-Trp-Glu]-NH2	DMX7IVO	Discovery agent	N.A.	Investigative	[20]
C[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2	DMUESCH	Discovery agent	N.A.	Investigative	[20]
C[Nle-Asp-D-Nal(2')-Arg-Trp-Glu]-NH2	DM8SXLR	Discovery agent	N.A.	Investigative	[20]
C[Nle-Asp-D-Phe-Arg-Trp-Glu]-NH2	DMXJAOI	Discovery agent	N.A.	Investigative	[20]
C[Nle-Gln-D-Nal(2')-Arg-Trp-Glu]-NH2	DMM19SJ	Discovery agent	N.A.	Investigative	[20]
C[Nle-Glu-D-Nal(2')-Arg-Trp-Glu]-NH2	DMHNCAG	Discovery agent	N.A.	Investigative	[20]
C[Nle-His-D-Nal(2')-Arg-Trp-Glu]-NH2	DM36HBK	Discovery agent	N.A.	Investigative	[20]
C[Nle-His-D-Phe-Arg-Trp-Glu]-NH2	DM5HRNM	Discovery agent	N.A.	Investigative	[20]
C[Nle-Nle-D-Nal(2')-Arg-Trp-Glu]-NH2	DM73ZMG	Discovery agent	N.A.	Investigative	[20]
C[Nle-Nle-D-Phe-Arg-Trp-Glu]-NH2	DMDPBVS	Discovery agent	N.A.	Investigative	[20]
C[Nle-Pro-D-Nal(2')-Arg-Trp-Glu]-NH2	DMPZ4VB	Discovery agent	N.A.	Investigative	[20]
C[Nle-Pro-D-Phe-Arg-Trp-Glu]-NH2	DMZWMV0	Discovery agent	N.A.	Investigative	[20]
C[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2	DMSIGJW	Discovery agent	N.A.	Investigative	[20]
C[Nle-Val-D-Phe-Arg-Trp-Glu]-NH2	DM45ZLW	Discovery agent	N.A.	Investigative	[20]
C[Ser-Tyr-Thr-His-Dphe-Arg-Trp-Thr-Ile-Pro]	DMO7BMZ	Discovery agent	N.A.	Investigative	[21]
C[Thr-Tyr-Thr-His-DNaf-Arg-Trp-Thr-Ile-Pro]	DMRY95I	Discovery agent	N.A.	Investigative	[21]
D-Phe-Arg-2-Nal-NHCH3	DMLK428	Discovery agent	N.A.	Investigative	[22]
GPYRMEHFRWGSPPKD-NH2	DMLRTPH	Discovery agent	N.A.	Investigative	[12]
His-DPhe-Arg-Trp	DMRJGOP	Discovery agent	N.A.	Investigative	[23]
Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2	DMHW2DU	Discovery agent	N.A.	Investigative	[6]
HS014	DMM3FD2	Discovery agent	N.A.	Investigative	[24]
MCL-129	DMQZC0U	Discovery agent	N.A.	Investigative	[25]
MCL0129	DMFTPMX	Discovery agent	N.A.	Investigative	[17]
Melanocortin-4 Receptor antagonist	DM2ES7Z	Anorexia nervosa cachexia	6B80	Investigative	[26]
MK-10	DMI7859	Discovery agent	N.A.	Investigative	[27]
MK-11	DM4FG32	Discovery agent	N.A.	Investigative	[27]
ML-253764	DMK6YC1	Discovery agent	N.A.	Investigative	[21]
MT-II	DMKT1DA	Female sexual arousal dysfunction	HA01.1	Investigative	[28]
NDP-alpha-MSH	DMTMHW2	Discovery agent	N.A.	Investigative	[29]
NDP-SYSMEHFRWGKPVG	DMRV16G	Discovery agent	N.A.	Investigative	[12]
Ser-Tyr-Ser-Nle-Glu-His-Dphe-Arg	DMS509U	Discovery agent	N.A.	Investigative	[23]
THIQ	DMP8LSF	Erectile dysfunction	HA01.1	Investigative	[17]
Tic-D-Phe-Arg-2-Nal-NHCH3	DMMFCHU	Discovery agent	N.A.	Investigative	[30]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Type 2 diabetes	5A11	Liver tissue	5.64E-01	-0.04	-0.18

References

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• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [4] Novel anti-obesity drugs. Expert Opin Investig Drugs. 2000 Jun;9(6):1317-26.
• [5] Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole. Neuropsychopharmacology. 2015 Jul;40(8):1856-65.
• [6] Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivo activity. Bioorg Med Chem Lett. 2006 Oct 1;16(19):5088-92.
• [7] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [8] Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss. J Med Chem. 2023 Mar 9;66(5):3195-3211.
• [9] The 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.
• [10] Privileged structure based ligands for melanocortin receptors--substituted benzylic piperazine derivatives. Bioorg Med Chem Lett. 2005 Nov 15;15(22):4973-8.
• [11] 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 rec... J Med Chem. 2010 Sep 9;53(17):6386-97.
• [12] Discovery of a beta-MSH-derived MC-4R selective agonist. J Med Chem. 2005 May 5;48(9):3095-8.
• [13] Design and synthesis of potent and selective 1,3,4-trisubstituted-2-oxopiperazine based melanocortin-4 receptor agonists. Bioorg Med Chem Lett. 2006 Sep 1;16(17):4668-73.
• [14] Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. J Med Chem. 1997 Jul 4;40(14):2133-9.
• [15] Substitution of arginine with proline and proline derivatives in melanocyte-stimulating hormones leads to selectivity for human melanocortin 4 rece... J Med Chem. 2009 Jun 25;52(12):3627-35.
• [16] Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007 Sep;12(17-18):757-66.
• [17] URL: 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).
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• [20] Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities. J Med Chem. 2006 Mar 23;49(6):1946-52.
• [21] 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... J Med Chem. 2006 Feb 9;49(3):911-22.
• [22] Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic ap... J Med Chem. 2006 Jul 27;49(15):4745-61.
• [23] Squalene-derived flexible linkers for bioactive peptides. Bioorg Med Chem Lett. 2007 Jun 15;17(12):3310-3.
• [24] Long-term administration of MC4 receptor antagonist HS014 causes hyperphagia and obesity in rats. Neuroreport. 1999 Mar 17;10(4):707-11.
• [25] Structure-activity relationships of novel piperazines as antagonists for the melanocortin-4 receptor. Bioorg Med Chem. 2007 Mar 1;15(5):1989-2005.
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• [27] Novel cyclic templates of alpha-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors. J Med Chem. 2002 Jun 6;45(12):2644-50.
• [28] Molecular determinants of ligand binding to the human melanocortin-4 receptor. Biochemistry. 2000 Dec 5;39(48):14900-11.
• [29] 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... J Med Chem. 2008 Nov 27;51(22):7094-8.
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