Identification of antagonists for melanocortin MC₃, MC₄ and MC₅ receptors

Antagonists for the melanocortin receptor family were identified by analysis of the effects of four melanocortin analogues on α-MSH(α-melanocyte-stimulating hormone)-induced cAMP accumulation in 293 human embryonal kidney (HEK) cells that expressed either the rat melanocortin MC₃ receptor, the human melanocortin MC₄ receptor or the ovine melanocortin MC₅ receptor. Two peptides, [D-Arg⁸]ACTH(adrenocorticotrope hormone)-(4-10) and [Pro^8,10, Gly⁹]ACTH-(4-10), antagonized the action of α-MSH on the melanocortin MC₄ and MC₅ receptors, but not the melanocortin MC₃ receptor. [Ala⁶]ACTH-(4-10) inhibited the α-MSH activation of the melanocortin MC₃ and MC₅, but only weakly antagonized the activation of the melanocortin MC₄ receptor. [Phe-I⁷]ACTH-(4-10) antagonized the melanocortin MC₃, MC₄ and MC₅ receptors equally well. These antagonists were also tested to block a behavioral response induced by α-MSH. α-MSH-induced excessive grooming behavior in rats was inhibited by [Phe-I⁷]ACTH-(4-10), [D-Arg⁸]ACTH-(4-10) and [Pro^8,10,Gly⁹]ACTH-(4-10), but not by [Ala⁶]ACTH-(4-10). This suggests that α-MSH-induced excessive grooming behavior is mediated by melanocortin MC₄ receptors.