Melanotan I

Melanotan I, also known by the nonproprietary name afamelanotide, is a synthetic linear 13-residue analog of alpha-melanocyte-stimulating hormone (alpha-MSH) with the sequence Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 (C78H111N21O19, about 1646.8 g/mol). It differs from the endogenous hormone at two positions, with norleucine replacing methionine at position 4 and D-phenylalanine replacing L-phenylalanine at position 7, and is therefore also designated [Nle4, D-Phe7]-alpha-MSH or NDP-MSH. The analog was first reported in 1980 by Sawyer, Hruby, Hadley and colleagues.

Melanotan I in the research literature

In its original characterization, [Nle4, D-Phe7]-alpha-MSH resisted degradation by serum enzymes and was about 26 times as potent as alpha-MSH in a mouse cell adenylate cyclase assay. Its principal target is the melanocortin-1 receptor (MC1R), a seven-transmembrane G-protein-coupled receptor. Site-directed mutagenesis of MC1R showed that the acidic residues Glu94, Asp117 and Asp121, together with aromatic residues in transmembrane helices 4 to 6, contribute to NDP-MSH binding affinity and potency.

NDP-MSH is not restricted to MC1R. It is also a high-affinity agonist at the melanocortin-4 receptor, and cryo-electron microscopy structures of MC4R-Gs complexes bound to NDP-alpha-MSH have described its binding mode, the role of transmembrane helix 3 and a calcium ion cofactor in ligand recognition, and TM6-regulated receptor activation.