Melanocortin receptor

Melanocortin receptors are members of the rhodopsin family of 7-transmembrane G protein-coupled receptors.

There are five known members of the melanocortin receptor system^[1] each with differing specificities for melanocortins:^[2][3][4]

• MC1R. MC1R is associated with pigmentation genetics.
• MC2R. MC2R is also known as the ACTH receptor or corticotropin receptor because it is specific for ACTH alone.
• MC3R. MC3R is associated with childhood growth, accrual of lean mass and onset of puberty.^[5]
• MC4R. Defects in MC4R are a cause of autosomal dominant obesity, accounting for 6% of all cases of early-onset obesity.^[6]
• MC5R. MC5R

These receptors are inhibited by endogenous inverse agonists agouti signalling peptide and agouti-related peptide,^[7] and activated by synthetic (i.e. afamelanotide) and endogenous agonist melanocyte-stimulating hormones.^[8]

Selective ligands

Several selective ligands for the melanocortin receptors are known,^{[9][10][11][12]} and some synthetic compounds have been investigated as potential tanning, anti-obesity and aphrodisiac drugs, with tanning effects mainly from stimulation of MC₁,^[13] while anorectic and aphrodisiac effects appear to involve both MC₃ and MC₄.^[14] MC₁, MC₃ and MC₄ are widely expressed in the brain, and are also thought to be responsible for effects on mood and cognition.^{[15][16][17][18]}

Agonists

Non-selective

• α-MSH
• β-MSH
• γ-MSH
• Afamelanotide
• Bremelanotide
• Melanotan II
• Modimelanotide
• Setmelanotide

MC₁-selective

• BMS-470,539

MC₄-selective

• PF-00446687
• PL-6983
• THIQ

Unknown (but for certain MC₂-acting)

• Alsactide
• Tetracosactide

Antagonists and inverse agonists

Non-selective

• Agouti-related peptide
• Agouti signalling peptide

MC₂-selective

• Atumelnant (CRN04894)

MC₄-selective

• HS-014
• HS-024
• MCL-0042^[19]
• MCL-0129^[20]
• MPB-10
• SHU-9119 (agonist at MC₁ and MC₅, antagonist at MC₃ and MC₄)

Unknown

• Semax