ASP(10) IN LYS-GAMMA(2)-MSH DETERMINES SELECTIVE ACTIVATION OF THE MELANOCORTIN MC3 RECEPTOR

The melanocortin MC3 and MC4 receptors are the main melanocortin recep tors expressed in brain. Of the endogenous melanocortins, gamma(2)-mel anocortin stimulating hormone (MSH) selectively activates the melanoco rtin MC3 receptor, whereas alpha- and beta-MSH activate all melanocort in receptors. The aim was to gain an insight into the contribution of amino acids in positions 5 and 10 of melanocortins to the selectivity of [Nle(4)]Lys-gamma(2)-MSH for the melanocortin MC3 receptor versus t he melanocortin MC4 receptor. Introduction of Asp(10) into [Nle(4)]alp ha-MSH as in [Nle(4),Gly(5),Asp(10)]alpha-MSH selectively increased th e EC50 value for the melanocortin MC4 receptor. Conversely, removal of Asp(10), as in [Nle(4),Gly(10)]Lys-gamma(2)-MSH, selectively decrease d the EC50 value for the melanocortin MC4 receptor. Thus, Asp(10) in L ys-gamma(2)-MSH determined selectivity for the melanocortin MC3 recept or versus the melanocortin MC4 receptor. (C) 1998 Elsevier Science B.V . All rights reserved.