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

Antagonists for the melanocortin receptor family were identified by an alysis of the effects of four melanocortin analogues on alpha-MSH(alph a-melanocyte-stimulating hormone)-induced cAMP accumulation in 293 hum an embryonal kidney (HEK) cells that expressed either the rat melanoco rtin MC(3) receptor, the human melanocortin MC(4), receptor or the ovi ne melanocortin MC(5), receptor. Two peptides, [D-Arg(8)]ACTH(adrenoco rticotrope hormone)-(4-10) and [Pro(8,10),Gly(9)]ACTH-(4-10), antagoni zed the action of alpha-MSH on the melanocortin MC(4) and MC(5) recept ors, but not the melanocortin MC(3) receptor. [Ala(6)]ACTH-(4-10) inhi bited the alpha-MSH activation of the melanocortin MC(3) and MC(5), bu t only weakly antagonized the activation of the melanocortin MC(4) rec eptor. [Phe-I-7]ACTH-(4-10) antagonized the melanocortin MC(3), MC(4) and MC(5) receptors equally well. These antagonists were also tested t o 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.