Minimization of MC1R selectivity by modification of the core structure of α-MSH-ND Original Research Article

Background: Melanocortin, through its distinct receptor subtypes, has many different effects. Receptor-selective ligands are required to reduce the undesirable effects of melanocortin. To investigate which conformation is preferable to a given melanocortin receptor subtype, a structural and functional analysis of the ligand–receptor interactions was made by studying the biological activity, the nuclear magnetic resonance structures, and the patterns of the ligand–receptor interaction for each receptor subtype by homology modeling analysis. Results: Among the several analogues examined, [Gln6]α-melanocyte-stimulating hormone (MSH)-ND was found to have 10 000 times less biological activity than α-MSH-ND for the MC1R, whereas, the potencies of both oligopeptides were comparable in both the melanocortin-3 receptor (MC3R) and MC4R. [Gln6]α-MSH-ND exhibited a type I′ β-turn that was similar to the type I β-turn structure of α-MSH-ND. However, a remarkable structural difference was observed with respect to the side chain orientations of the sixth and seventh residues of [Gln6]α-MSH-ND, which were found to be mirror images of α-MSH-ND. By homology modeling analysis, the His6 of α-MSH-ND was found to interact with the TM2 regions of all three receptors (Glu94 of MC1R, Glu94 of MC3R, and Glu100 of MC4R), but [Gln6]α-MSH-ND did not. The phenyl ring of the D-Phe7 residue of [Gln6]α-MSH-ND revealed an interaction with the TM3 regions of both the MC3R and MC4R (Ser122 of MC3R or Ser127 of MC4R). However, in the MC1R, these serine residues corresponded to Val122, which contains two methyl groups that induce steric hindrance with D-Phe7 of [Gln6]α-MSH-ND. This is a possible explanation for the biological activity of [Gln6]α-MSH-ND for the MC1R being significantly lower than that for either the MC3R or MC4R. Conclusions: Minimization of the MC1R selectivity whilst preserving its comparable potency for both the MC3R and MC4R could be achieved by modifying the D-Phe7 orientation of α-MSH-ND, while maintaining the ‘type I β-turn’-like structure.