Melanotan II

Melanotan II (MT-II) is a synthetic cyclic heptapeptide analog of alpha-MSH, Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 (C50H69N15O9, about 1024.18 g/mol). It is built on the alpha-MSH 4-10 core sequence, carries norleucine at position 4 and D-phenylalanine at position 7, and is cyclized through a lactam bridge between the side chains of Asp5 and Lys10. This cyclization constrains the conformation of the central melanocortin core sequence, a structural feature that receptor-selectivity studies have used to explain how MT-II interacts differently with individual melanocortin receptor subtypes.

Melanotan II in the research literature

Structure-activity work characterizes MT-II as a potent, non-selective agonist across the melanocortin receptors, and it has served as a parent scaffold for analogs with altered selectivity. Replacing its lactam cyclization with xylene-derived thioether linkers yielded compounds with binding affinities from the low nanomolar to the sub-micromolar range and, in one case, functional selectivity for MC1R. At MC1R, mutagenesis showed that acidic receptor residues Glu94, Asp117 and Asp121 contribute to MT-II binding and potency, as with other melanocortin agonists.

At the brain melanocortin receptors, mutating Tyr268 of MC4R reduced affinity for cyclic core-constrained peptides including MT-II, which also showed lower affinity at MC3R, work used to model how conformational presentation of the core sequence governs MC3R versus MC4R selectivity.