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Research Catalog

Molecular mechanism

Melanocortin receptors

A family of five G protein-coupled receptors, MC1R through MC5R. ACTH recognition and signaling at MC2R depend on the accessory protein MRAP. Native hormones, peptide analogs and nonpeptide ligands differ in receptor-subtype recognition and functional direction; binding affinity, agonism and antagonism must be interpreted separately in the experimental system studied.

Type: receptorPublished: 2026-09-13Literature/identifier verification: 2026-09-13

See this target on the receptor map

MC1RMC2RMC3RMC4RMC5RMCR

01

Neutral molecular overview

A family of five G protein-coupled receptors, MC1R through MC5R. ACTH recognition and signaling at MC2R depend on the accessory protein MRAP. Native hormones, peptide analogs and nonpeptide ligands differ in receptor-subtype recognition and functional direction; binding affinity, agonism and antagonism must be interpreted separately in the experimental system studied.

02

Target identifiers

Gene symbols
MC1R, MC2R, MC3R, MC4R, MC5R

03

Related compounds

Compound

Melanotan I (Afamelanotide)

Afamelanotide, widely supplied as Melanotan I, is a linear thirteen-residue analog of alpha-melanocyte-stimulating hormone carrying norleucine and D-phenylalanine substitutions.

Compound

alpha-MSH

alpha-MSH is the endogenous thirteen-residue melanocortin peptide hormone from which several of the synthetic compounds in this library are derived.

Compound

PT-141 (Bremelanotide)

PT-141, canonically bremelanotide, is a synthetic cyclic heptapeptide melanocortin receptor agonist, structurally the C-terminal free acid of the Melanotan II lactam scaffold.

Compound

Cosyntropin (ACTH 1-24)

Cosyntropin is the synthetic 1-24 fragment of adrenocorticotropic hormone, the melanocortin ligand of the MC2R branch.

Compound

Melanotan II

Melanotan II is a synthetic cyclic heptapeptide analog of alpha-melanocyte-stimulating hormone, closed by a lactam bridge between an aspartate and a lysine side chain.

Compound

Setmelanotide

Setmelanotide is a synthetic disulfide-cyclized octapeptide characterised as an MC4R-preferring melanocortin receptor agonist. A review by Swan et al. (PMID 38834138) describes setmelanotide as an analogue of alpha-melanocyte-stimulating hormone; that is a review-level parent attribution, not a residue-by-residue design account.

Compound

SHU9119

SHU9119 is a cyclic lactam melanocortin analog whose receptor behaviour is subtype-dependent: antagonist at some melanocortin receptors and agonist at others. Gimenez et al. (PMID 35404053) describe SHU9119 as a cyclic heptapeptide analogue of alpha-melanocyte-stimulating hormone.

Compound

THIQ

THIQ is a nonpeptide small-molecule agonist at the melanocortin-4 receptor, included here as the nonpeptide comparator to the melanocortin peptides.

04

Related mechanisms

No related mechanism is declared in this seed record.

05

Verified bibliography

  1. Reference 1

    Structure-function studies on the cyclic peptide MT-II, lactam derivative of alpha-melanotropin.

    Bednarek MA, Silva MV, Arison B, MacNeil T, Kalyani RN, Huang RR, Weinberg DH

    Peptides · 1999 · Journal Article

    current
    PMID 10447101DOI 10.1016/s0196-9781(99)00048-0Melanotan IIMC1R

  2. Reference 2

    Structural insights into ligand recognition and activation of the melanocortin-4 receptor.

    Zhang H, Chen LN, Yang D, Mao C, Shen Q, Feng W, Shen DD, Dai A, Xie S, Zhou Y, Qin J, Sun JP, Scharf DH, Hou T, Zhou T, Wang MW, Zhang Y

    Cell research · 2021-08-25 · Journal Article

    current
    PMID 34433901PMC8563965DOI 10.1038/s41422-021-00552-3PT-141 (Bremelanotide)Melanotan I (Afamelanotide)alpha-MSHTHIQSetmelanotideMC1R

  3. Reference 3

    Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide.

    Heyder NA, Kleinau G, Speck D, Schmidt A, Zschunke S, Szczepek M, Bauer B, Koch A, Gallandi M, Kwiatkowski D, Bürger J, Mielke T, Beck-Sickinger AG, Hildebrand PW, Spahn CMT, Hilger D, Schacherl M, Biebermann H, Hilal T, Kühnen P, Kobilka BK, Scheerer P

    Cell research · 2021-09-24 · Journal Article

    current
    PMID 34561620PMC8563958DOI 10.1038/s41422-021-00569-8PT-141 (Bremelanotide)Melanotan I (Afamelanotide)SetmelanotideMC1R

  4. Reference 4

    4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity.

    Sawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH, Heward CB, Burnett JB, Hadley ME

    Proceedings of the National Academy of Sciences of the United States of America · 1980-10 · Journal Article

    current
    PMID 6777774PMC350149DOI 10.1073/pnas.77.10.5754Melanotan I (Afamelanotide)MC1R

  5. Reference 5

    Molecular basis for the interaction of [Nle4,D-Phe7]melanocyte stimulating hormone with the human melanocortin-1 receptor.

    Yang Yk, Dickinson C, Haskell-Luevano C, Gantz I

    The Journal of biological chemistry · 1997-09-12 · Journal Article

    current
    PMID 9287296DOI 10.1074/jbc.272.37.23000Melanotan I (Afamelanotide)MC1R

  6. Reference 6

    Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor.

    Ma S, Chen Y, Dai A, Yin W, Guo J, Yang D, Zhou F, Jiang Y, Wang MW, Xu HE

    Cell research · 2021-08-27 · Journal Article

    current
    PMID 34453129PMC8486761DOI 10.1038/s41422-021-00557-yMelanotan I (Afamelanotide)alpha-MSHSHU9119MC1R

  7. Reference 7

    CLIPSing Melanotan-II to Discover Multiple Functionally Selective hMCR Agonists.

    Tomassi S, Dimmito MP, Cai M, D'Aniello A, Del Bene A, Messere A, Liu Z, Zhu T, Hruby VJ, Stefanucci A, Cosconati S, Mollica A, Di Maro S

    Journal of medicinal chemistry · 2022-02-21 · Journal Article

    current
    PMID 35188390DOI 10.1021/acs.jmedchem.1c01848Melanotan IIMC1R

  8. Reference 8

    Goldilocks-Inspired Design of Mid-Size Macrocycles for Selective Targeting of Human Melanocortin Receptors.

    Merlino F, Jia L, Boccino I, Carotenuto A, Tammaro F, Santoro F, Thompson PE, Grieco P

    Journal of medicinal chemistry · 2026-08-13 · Journal Article

    current
    PMID 42340853PMC13492293DOI 10.1021/acs.jmedchem.6c01074Melanotan IIPT-141 (Bremelanotide)MC1R

  9. Reference 9

    Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors.

    Hruby VJ, Lu D, Sharma SD, Castrucci AL, Kesterson RA, al-Obeidi FA, Hadley ME, Cone RD

    Journal of medicinal chemistry · 1995-09-01 · Journal Article

    current
    PMID 7658432DOI 10.1021/jm00018a005SHU9119MC1R

  10. Reference 10

    Determination of the melanocortin-4 receptor structure identifies Ca(2+) as a cofactor for ligand binding.

    Yu J, Gimenez LE, Hernandez CC, Wu Y, Wein AH, Han GW, McClary K, Mittal SR, Burdsall K, Stauch B, Wu L, Stevens SN, Peisley A, Williams SY, Chen V, Millhauser GL, Zhao S, Cone RD, Stevens RC

    Science (New York, N.Y.) · 2020-04-24 · Journal Article

    current
    PMID 32327598PMC7567314DOI 10.1126/science.aaz8995SHU9119MC1R

  11. Reference 11

    Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.

    Israeli H, Degtjarik O, Fierro F, Chunilal V, Gill AK, Roth NJ, Botta J, Prabahar V, Peleg Y, Chan LF, Ben-Zvi D, McCormick PJ, Niv MY, Shalev-Benami M

    Science (New York, N.Y.) · 2021-04-15 · Journal Article

    current
    PMID 33858992DOI 10.1126/science.abf7958SetmelanotideMC1R

  12. Reference 12

    Interactions of human melanocortin 4 receptor with nonpeptide and peptide agonists.

    Pogozheva ID, Chai BX, Lomize AL, Fong TM, Weinberg DH, Nargund RP, Mulholland MW, Gantz I, Mosberg HI

    Biochemistry · 2005-08-30 · Journal Article

    current
    PMID 16114870PMC2532597DOI 10.1021/bi0501840THIQMC1R

  13. Reference 13

    Key amino acid residues in the melanocortin-4 receptor for nonpeptide THIQ specific binding and signaling.

    Yang Y, Cai M, Chen M, Qu H, McPherson D, Hruby V, Harmon CM

    Regulatory peptides · 2009-03-20 · Journal Article

    current
    PMID 19303903PMC3216638DOI 10.1016/j.regpep.2009.03.006THIQMC1R

  14. Reference 14

    Adrenocorticotropic Hormone (ACTH) Responses Require Actions of the Melanocortin-2 Receptor Accessory Protein on the Extracellular Surface of the Plasma Membrane.

    Malik S, Dolan TM, Maben ZJ, Hinkle PM

    The Journal of biological chemistry · 2015-09-30 · Journal Article

    current
    PMID 26424796PMC4646036DOI 10.1074/jbc.m115.668491Cosyntropin (ACTH 1-24)MC1R

  15. Reference 15

    Use of chimeric melanocortin-2 and -4 receptors to identify regions responsible for ligand specificity and dependence on melanocortin 2 receptor accessory protein.

    Hinkle PM, Serasinghe MN, Jakabowski A, Sebag JA, Wilson KR, Haskell-Luevano C

    European journal of pharmacology · 2011-01-03 · Journal Article

    current
    PMID 21211532PMC3095721DOI 10.1016/j.ejphar.2010.10.113alpha-MSHCosyntropin (ACTH 1-24)MC1R

  16. Reference 16

    Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1.

    Luo P, Feng W, Ma S, Dai A, Wu K, Chen X, Yuan Q, Cai X, Yang D, Wang MW, Eric Xu H, Jiang Y

    Cell research · 2023-01-02 · Journal Article

    current
    PMID 36588120PMC9810661DOI 10.1038/s41422-022-00751-6Cosyntropin (ACTH 1-24)MC1R

  17. Reference 17

    Dissection of the anti-inflammatory effect of the core and C-terminal (KPV) alpha-melanocyte-stimulating hormone peptides.

    Getting SJ, Schiöth HB, Perretti M

    The Journal of pharmacology and experimental therapeutics · 2003-05-15 · Journal Article

    current
    PMID 12750433DOI 10.1124/jpet.103.051623alpha-MSHSHU9119KPVMelanotan IIMC1R

Study models of these references

What kind of experiment each cited paper reports, taken from its abstract unless marked. Not a summary of results.

ReferenceStudy models
Bednarek MA et al. 1999Study models reported: in vitro · from the abstract
Zhang H et al. 2021Study models reported: in vitro · from the abstract
Heyder NA et al. 2021Study models reported: in vitro · from the abstract
Sawyer TK et al. 1980Study models reported: in vitro · from the full text
Yang Yk et al. 1997Study models reported: in vitro · from the abstract
Ma S et al. 2021Study models reported: in vitro · from the abstract
Tomassi S et al. 2022Study models reported: in vitro · from the abstract
Merlino F et al. 2026Study models reported: in vitro · from the abstract
Hruby VJ et al. 1995Study models reported: in vitro · from the abstract
Yu J et al. 2020Study models reported: in vitro · from the abstract
Israeli H et al. 2021Study models reported: in vitro · from the abstract
Pogozheva ID et al. 2005Study models reported: in vitro · from the abstract
Yang Y et al. 2009Study models reported: in vitro · from the abstract
Malik S et al. 2015Study models reported: in vitro · from the abstract
Hinkle PM et al. 2011Study models reported: in vitro · from the abstract
Luo P et al. 2023Study models reported: in vitro · from the abstract
Getting SJ et al. 2003Study models reported: in vitro; animal (mouse) · from the abstract

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Related glossary terms

AgonistLigandG-protein-coupled receptor

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Related Purely Peptides research articles

No existing Research Article is mapped to this mechanism seed record.