Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT0MV2T)

• DTT Name: Melanocortin receptor 1 (MC1R)
• Synonyms: Melanotropin receptor; Melanocyte-stimulating hormone receptor; Melanocortin-1 receptor; MSHR; MSH-R; MC1-R
• Gene Name: MC1R
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: MSHR_HUMAN
• TTD ID: T35842
• Sequence:
  MAVQGSQRRLLGSLNSTPTAIPQLGLAANQTGARCLEVSISDGLFLSLGLVSLVENALVV
  ATIAKNRNLHSPMYCFICCLALSDLLVSGSNVLETAVILLLEAGALVARAAVLQQLDNVI
  DVITCSSMLSSLCFLGAIAVDRYISIFYALRYHSIVTLPRARRAVAAIWVASVVFSTLFI
  AYYDHVAVLLCLVVFFLAMLVLMAVLYVHMLARACQHAQGIARLHKRQRPVHQGFGLKGA
  VTLTILLGIFFLCWGPFFLHLTLIVLCPEHPTCGCIFKNFNLFLALIICNAIIDPLIYAF
  HSQELRRTLKEVLTCSW
• Function: The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Receptor for MSH (alpha, beta and gamma) and ACTH.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Melanogenesis (hsa04916)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Afamelanotide	DMVWHTG	Erythropoietic porphyrias	5C58.12	Approved	[2]
Bremelanotide	DM20LIM	Hypoactive sexual desire dysfunction	HA00	Approved	[3]

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dersimelagon	DMMO0SU	Erythropoietic protoporphyria	5C58.12	Phase 3	[4]
PL8177	DML5V22	Ulcerative colitis	DD71	Phase 2	[5]
AP-1030	DMBGA35	Metabolic disorder	5C50-5D2Z	Phase 1/2	[6]

36 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ac-dR[CEHdFRWC]-NH2	DM7XY41	Discovery agent	N.A.	Investigative	[7]
Ac-His-D-Phe-Arg-2-Nal-NHCH3	DMAQR29	Discovery agent	N.A.	Investigative	[8]
Ac-His-DPhe-Arg-Trp-NH2	DMMP0D8	Discovery agent	N.A.	Investigative	[9]
Ac-Nle-c[Asp-His-DNaI(2')-Pro-Trp-Lys]-NH2	DMLYGPW	Discovery agent	N.A.	Investigative	[10]
Ac-Nle-c[Asp-His-DNal(2')-Pro-Trp-Lys]-NH2	DMOVI7Y	Discovery agent	N.A.	Investigative	[10]
Ac-R[CEHdFRWC]-NH2	DMBFUD0	Discovery agent	N.A.	Investigative	[7]
Ac-Tyr-D-Phe-Arg-2-Nal-NHCH3	DMIH5CD	Discovery agent	N.A.	Investigative	[8]
Ac-YCit[CEHdFRWC]-NH2	DMAVPXL	Discovery agent	N.A.	Investigative	[7]
Ac-YK[CEHdFRWC]-NH2	DM5SJX8	Discovery agent	N.A.	Investigative	[7]
Ac-YRC(Me)*EHdFRWC(Me)NH2	DMWJ8UR	Discovery agent	N.A.	Investigative	[7]
Ac-YRMEHdFRWG-NH2	DMN2UKC	Discovery agent	N.A.	Investigative	[7]
Ac-YRMEHdFRWGSPPKD-NH2	DMDH5B3	Discovery agent	N.A.	Investigative	[7]
Ac-YR[CEH(d-2alpha-Nal)RWC]-NH2	DMVQ4KG	Discovery agent	N.A.	Investigative	[7]
Ac-YR[CEH(pCl-dF)RWC]-NH2	DM25JXM	Discovery agent	N.A.	Investigative	[7]
Ac-YR[CEH(pF-dF)RWC]-NH2	DMXCF9T	Discovery agent	N.A.	Investigative	[7]
Ac-YR[CEHdFRWC]-NH2	DMBMY73	Discovery agent	N.A.	Investigative	[7]
Ac-YR[CEHdFRWC]SPPKD-NH2	DMDO468	Discovery agent	N.A.	Investigative	[7]
Ac-YR[CEHFRWC]-NH2	DMH0EAI	Discovery agent	N.A.	Investigative	[7]
Ac-[CEHdFRWC]-NH2	DMRLOGP	Discovery agent	N.A.	Investigative	[7]
AEKKDEGPYRMEHFRWGSPPKD	DMZ8SV3	Discovery agent	N.A.	Investigative	[7]
AP-1189	DMRZMKT	Atopic dermatitis	EA80	Investigative	[11]
C[CO-(CH2)2-CO-Nle-D-Nal(2)-Arg-Trp-Lys]-NH2	DMHARQX	Discovery agent	N.A.	Investigative	[12]
C[CO-2,3-pyrazine-CO-D-Nal(2)-Arg-Trp-Lys]-NH2	DM1VCJP	Discovery agent	N.A.	Investigative	[12]
C[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]-NH2	DM8AMGF	Discovery agent	N.A.	Investigative	[12]
C[CO-o-C6H4-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2	DMD6OW4	Discovery agent	N.A.	Investigative	[12]
C[Nle-Arg-D-Nal(2')-Arg-Trp-Glu]-NH2	DMX7IVO	Discovery agent	N.A.	Investigative	[13]
C[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2	DMUESCH	Discovery agent	N.A.	Investigative	[13]
C[Nle-Gln-D-Nal(2')-Arg-Trp-Glu]-NH2	DMM19SJ	Discovery agent	N.A.	Investigative	[13]
C[Nle-Gln-D-Phe-Arg-Trp-Glu]-NH2	DMSGWZE	Discovery agent	N.A.	Investigative	[13]
C[Nle-Nle-D-Nal(2')-Arg-Trp-Glu]-NH2	DM73ZMG	Discovery agent	N.A.	Investigative	[13]
C[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2	DMSIGJW	Discovery agent	N.A.	Investigative	[13]
D-Phe-Arg-2-Nal-NHCH3	DMLK428	Discovery agent	N.A.	Investigative	[14]
GPYRMEHFRWGSPPKD-NH2	DMLRTPH	Discovery agent	N.A.	Investigative	[7]
MT-II	DMKT1DA	Female sexual arousal dysfunction	HA01.1	Investigative	[15]
NDP-SYSMEHFRWGKPVG	DMRV16G	Discovery agent	N.A.	Investigative	[7]
Tic-D-Phe-Arg-2-Nal-NHCH3	DMMFCHU	Discovery agent	N.A.	Investigative	[16]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Atopic dermatitis	EA90	Skin	1.44E-06	0.41	2.15

References

• [1] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [4] Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis. Arthritis Res Ther. 2022 Sep 1;24(1):210.
• [5] Pharmacokinetics of the Melanocortin Type 1 Receptor Agonist PL8177 After Subcutaneous Administration. Drugs R D. 2021 Dec;21(4):431-443.
• [6] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [7] Discovery of a beta-MSH-derived MC-4R selective agonist. J Med Chem. 2005 May 5;48(9):3095-8.
• [8] 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.
• [9] Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. J Med Chem. 1997 Jul 4;40(14):2133-9.
• [10] 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.
• [11] 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: 282).
• [12] Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 ... J Med Chem. 2008 Jan 24;51(2):187-95.
• [13] 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.
• [14] 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.
• [15] Design of potent linear alpha-melanotropin 4-10 analogues modified in positions 5 and 10. J Med Chem. 1989 Jan;32(1):174-9.
• [16] Synthesis of Tic-D-Phe Psi[CH2-CH2] isostere and its use in the development of melanocortin receptor agonists. Bioorg Med Chem Lett. 2006 Mar 15;16(6):1721-5.