Selective properties of C- and N-terminals and core residues of the melanocyte-stimulating hormone on binding to the human melanocortin receptor subtypes

We synthesised nine analogues of [Nle(4),D-Phe(7)]alpha-MSH (melanocyte-stimulating hormone) (NDP) where (1) the N- or C-terminals were deleted or exchanged by those of beta- or gamma-MSH and (2) the core residues His(6), Phe(7), Arg(8) and Trp(9) were individually substituted by Glu(6), beta-(2-naphthyl)-D-alanine (D-Nal(7)), Lys(8) and His(9), respectively. We tested these analogues in ligand binding assays with cells transiently expressing the human melanocortin MC1, MC3, MC4 and MC5 receptors. The results show that the N-terminal segment (Ser(1)-Tyr(2)-Ser(3)) of NDP was not important for binding to melanocortin MC1 and MC4 receptors whereas it affects binding to melanocortin MC3 and MC5 receptors. The C-terminal segment (Gly(10)-Lys(11)-Pro(12),Val(13)) of NDP was clearly important for binding to all the four melanocortin receptor subtypes. The data indicate that the low affinity of gamma-MSH for the melanocortin MC4 receptor is due to its C-terminal (Asp(10)-Arg(11)-Phe(12)). Substitution of D-Phe(7) by D-Nal(7) increased the affinity for the melanocortin MC4 receptor but not for the other melanocortin receptor subtypes. The other core residue substitutions lowered the affinity in a differentiated manner for each of the melanocortin receptors. These results are valuable for the molecular modelling and design of selective drugs for the melanocortin receptors. (C) 1998 Elsevier Science B.V. All rights reserved.