Target Information

Target General Information

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Target ID

T72458 (Former ID: TTDC00072)

Target Name

Melanocortin receptor 4 (MC4R)

Synonyms

MC4-R

Gene Name

MC4R

Target Type

Successful target

[1]

Disease

[+] 3 Target-related Diseases

Hypoactive sexual desire dysfunction [ICD-11: HA00]

Large intestine motility disorder [ICD-11: DB32]

Obesity [ICD-11: 5B80-5B81]

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.

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BioChemical Class

GPCR rhodopsin

UniProt ID

MC4R_HUMAN

Sequence

MVNSTHRGMHTSLHLWNRSSYRLHSNASESLGKGYSDGGCYEQLFVSPEVFVTLGVISLL
ENILVIVAIAKNKNLHSPMYFFICSLAVADMLVSVSNGSETIVITLLNSTDTDAQSFTVN
IDNVIDSVICSSLLASICSLLSIAVDRYFTIFYALQYHNIMTVKRVGIIISCIWAACTVS
GILFIIYSDSSAVIICLITMFFTMLALMASLYVHMFLMARLHIKRIAVLPGTGAIRQGAN
MKGAITLTILIGVFVVCWAPFFLHLIFYISCPQNPYCVCFMSHFNLYLILIMCNSIIDPL
IYALRSQELRKTFKEIICCYPLGGLCDLSSRY

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3D Structure

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AlphaFold

HIT2.0 ID

T17TKM

Drugs and Modes of Action

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Approved Drug(s)

[+] 3 Approved Drugs

Bremelanotide

Drug Info

Approved

Hypoactive sexual desire dysfunction

[2]

Methylnaltrexone bromide

Drug Info

Approved

Opioid-induced constipation

[3]

Setmelanotide

Drug Info

Approved

Obesity

[4]

Clinical Trial Drug(s)

[+] 4 Clinical Trial Drugs

AMG 386

Drug Info

Phase 3

Neuropathic pain

[5]

PF-446687

Drug Info

Phase 2

Female sexual arousal dysfunction

[6]

PMX-53

Drug Info

Phase 2

Atopic dermatitis

[7], [8]

AP-1030

Drug Info

Phase 1/2

Metabolic disorder

[9], [10]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

PT-14

Drug Info

Discontinued in Phase 2

Erectile dysfunction

[11]

Preclinical Drug(s)

[+] 3 Preclinical Drugs

IDDBCP-150101

Drug Info

Preclinical

Sexual dysfunction

[1]

Melanotetan II

Drug Info

Preclinical

Type-2 diabetes

[1]

Ro-27-3225

Drug Info

Preclinical

Obesity

[1]

Mode of Action

[+] 4 Modes of Action

Agonist

[+] 12 Agonist drugs

Bremelanotide

Drug Info

[2]

Methylnaltrexone bromide

Drug Info

[1]

Setmelanotide

Drug Info

[4]

Amylin

Drug Info

[12]

AMG 386

Drug Info

[1]

PT-14

Drug Info

[16]

IDDBCP-150101

Drug Info

[1]

Melanotetan II

Drug Info

[1]

Ro-27-3225

Drug Info

[1]

AMSH

Drug Info

[23]

MT-II

Drug Info

[22], [23], [35]

THIQ

Drug Info

[24]

Modulator

[+] 2 Modulator drugs

PF-446687

Drug Info

[13]

AP-1030

Drug Info

[15]

Inhibitor

[+] 64 Inhibitor drugs

PMX-53

Drug Info

[14]

1-Benzyl-4-methyl-piperazine

Drug Info

[17]

1-Methyl-4-(1-phenyl-ethyl)-piperazine

Drug Info

[17]

4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one

Drug Info

[18]

Ac-dR[CEHdFRWC]-NH2

Drug Info

[19]

Ac-His-D-Phe-Arg-2-Nal-NHCH3

Drug Info

[20]

Ac-His-DPhe-Arg-Trp-NH2

Drug Info

[21]

Ac-Nle-c[Asp-His-DNaI(2')-Pro-Trp-Lys]-NH2

Drug Info

[22]

Ac-Nle-c[Asp-His-DNal(2')-Pro-Trp-Lys]-NH2

Drug Info

[22]

AC-Nle-c[Asp-His-DPhe-Pro-Trp-Lys]-NH2

Drug Info

[22]

Ac-R[CEHdFRWC]-NH2

Drug Info

[19]

Ac-Tyr-D-Phe-Arg-2-Nal-NHCH3

Drug Info

[20]

Ac-YCit[CEHdFRWC]-NH2

Drug Info

[19]

Ac-YK[CEHdFRWC]-NH2

Drug Info

[19]

Ac-YRC(Me)*EHdFRWC(Me)NH2

Drug Info

[19]

Ac-YRMEHdFRWG-NH2

Drug Info

[19]

Ac-YRMEHdFRWGSPPKD-NH2

Drug Info

[19]

Ac-YR[CE(1-Me-H)dFRWC]-NH2

Drug Info

[19]

Ac-YR[CEH(d-2alpha-Nal)RWC]-NH2

Drug Info

[19]

Ac-YR[CEH(pCl-dF)RWC]-NH2

Drug Info

[19]

Ac-YR[CEH(pF-dF)RWC]-NH2

Drug Info

[19]

Ac-YR[CEHdFRWC]-NH2

Drug Info

[19]

Ac-YR[CEHdFRWC]SPPKD-NH2

Drug Info

[19]

Ac-YR[CEHFRWC]-NH2

Drug Info

[19]

Ac-[CEHdFRWC]-NH2

Drug Info

[19]

AEKKDEGPYRMEHFRWGSPPKD

Drug Info

[19]

C(his-D-phe-arg-trp-Abu)

Drug Info

[25]

C(his-D-phe-arg-trp-Ahp)

Drug Info

[25]

C(his-D-phe-arg-trp-Ahx)

Drug Info

[25]

C(his-D-phe-arg-trp-Aoc)

Drug Info

[25]

C(his-L-phe-arg-trp-Aoc)

Drug Info

[25]

C[CO-(CH2)2-CO-Nle-D-Nal(2)-Arg-Trp-Lys]-NH2

Drug Info

[26]

C[CO-(CH2)2-CO-Nle-D-Phe-Arg-Trp-Lys]-NH2

Drug Info

[26]

C[CO-(CH2)3-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2

Drug Info

[26]

C[CO-o-C6H4-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2

Drug Info

[26]

C[CO-o-C6H4-CO-Pro-D-Phe-Arg-Trp-Lys]-NH2

Drug Info

[26]

C[Nle-Arg-D-Nal(2')-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-Asp-D-Nal(2')-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-Asp-D-Phe-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-Gln-D-Nal(2')-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-Glu-D-Nal(2')-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-His-D-Nal(2')-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-His-D-Phe-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-Nle-D-Nal(2')-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-Nle-D-Phe-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-Pro-D-Nal(2')-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-Pro-D-Phe-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Nle-Val-D-Phe-Arg-Trp-Glu]-NH2

Drug Info

[27]

C[Ser-Tyr-Thr-His-Dphe-Arg-Trp-Thr-Ile-Pro]

Drug Info

[28]

C[Thr-Tyr-Thr-His-DNaf-Arg-Trp-Thr-Ile-Pro]

Drug Info

[28]

D-Phe-Arg-2-Nal-NHCH3

Drug Info

[29]

GPYRMEHFRWGSPPKD-NH2

Drug Info

[19]

His-DPhe-Arg-Trp

Drug Info

[30]

Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2

Drug Info

[14]

MCL-129

Drug Info

[32]

MK-10

Drug Info

[34]

MK-11

Drug Info

[34]

ML-253764

Drug Info

[28]

NDP-alpha-MSH

Drug Info

[36]

NDP-SYSMEHFRWGKPVG

Drug Info

[19]

Ser-Tyr-Ser-Nle-Glu-His-Dphe-Arg

Drug Info

[30]

Tic-D-Phe-Arg-2-Nal-NHCH3

Drug Info

[37]

Antagonist

[+] 4 Antagonist drugs

BL-6020

Drug Info

[24]

HS014

Drug Info

[31]

MCL0129

Drug Info

[24]

Melanocortin-4 Receptor antagonist

Drug Info

[33]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

Neuroactive ligand-receptor interaction

PID Pathway

[+] 1 PID Pathways

Syndecan-3-mediated signaling events

Reactome

[+] 2 Reactome Pathways

Peptide ligand-binding receptors

G alpha (s) signalling events

WikiPathways

[+] 4 WikiPathways

GPCRs, Class A Rhodopsin-like

Peptide GPCRs

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

Target QSAR Model

References

Top

REF 1

Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs. 2005 Aug;10(3):643-60.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019

REF 3

2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6.

REF 4

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020

REF 5

Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.

REF 6

ClinicalTrials.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 7

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. (Ligand id: 579).

REF 8

PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells. Mol Pharmacol. 2011 Jun;79(6):1005-13.

REF 9

REF 10

ClinicalTrials.gov (NCT00464958) One Year Extension Study To Protocol C2/5/TZ:MS-05. U.S. National Institutes of Health.

REF 11

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010143)

REF 12

Novel anti-obesity drugs. Expert Opin Investig Drugs. 2000 Jun;9(6):1317-26.

REF 13

Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole. Neuropsychopharmacology. 2015 Jul;40(8):1856-65.

REF 14

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.

REF 15

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 16

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.

REF 17

Privileged structure based ligands for melanocortin receptors--substituted benzylic piperazine derivatives. Bioorg Med Chem Lett. 2005 Nov 15;15(22):4973-8.

REF 18

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.

REF 19

Discovery of a beta-MSH-derived MC-4R selective agonist. J Med Chem. 2005 May 5;48(9):3095-8.

REF 20

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.

REF 21

Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. J Med Chem. 1997 Jul 4;40(14):2133-9.

REF 22

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.

REF 23

Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007 Sep;12(17-18):757-66.

REF 24

REF 25

Design of cyclic peptides with agonist activity at melanocortin receptor-4. Bioorg Med Chem Lett. 2006 Jul 15;16(14):3723-6.

REF 26

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.

REF 27

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.

REF 28

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.

REF 29

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.

REF 30

Squalene-derived flexible linkers for bioactive peptides. Bioorg Med Chem Lett. 2007 Jun 15;17(12):3310-3.

REF 31

Long-term administration of MC4 receptor antagonist HS014 causes hyperphagia and obesity in rats. Neuroreport. 1999 Mar 17;10(4):707-11.

REF 32

Structure-activity relationships of novel piperazines as antagonists for the melanocortin-4 receptor. Bioorg Med Chem. 2007 Mar 1;15(5):1989-2005.

REF 33

Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs. 2006 May;11(2):315-36.

REF 34

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.

REF 35

Molecular determinants of ligand binding to the human melanocortin-4 receptor. Biochemistry. 2000 Dec 5;39(48):14900-11.

REF 36

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.

REF 37

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.

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