IDENTIFICATION OF ANTAGONISTS FOR MELANOCORTIN MC(3), MC(4) AND MC(5) RECEPTORS

Antagonists for the melanocortin receptor family were identified by analysis of the effects of four melanocortin analogues on alpha-MSH(alpha-melanocyte-stimulating hormone)-induced cAMP accumulation in 293 human embryonal kidney (HEK) cells that expressed either the rat melanocortin MC(3) receptor, the human melanocortin MC(4), receptor or the ovine melanocortin MC(5), receptor. Two peptides, [D-Arg(8)]ACTH(adrenocorticotrope hormone)-(4-10) and [Pro(8,10),Gly(9)]ACTH-(4-10), antagonized the action of alpha-MSH on the melanocortin MC(4) and MC(5) receptors, but not the melanocortin MC(3) receptor. [Ala(6)]ACTH-(4-10) inhibited the alpha-MSH activation of the melanocortin MC(3) and MC(5), but only weakly antagonized the activation of the melanocortin MC(4) receptor. [Phe-I-7]ACTH-(4-10) antagonized the melanocortin MC(3), MC(4) and MC(5) receptors equally well. These antagonists were also tested to block a behavioral response induced by alpha-MSH. alpha-MSH-induced excessive grooming behavior in rats was inhibited by [Phe-I-7]ACTH-(4-10), [D-Arg(8)]ACTH-(4-10) and [Pro(8,10),Gly(9)]ACTH-(4-10), but not by [Ala(6)]ACTH-(4-10). This suggests that alpha-MSH-induced excessive grooming behavior is mediated by melanocortin MC(4) receptors.