DIFFERENTIAL-EFFECTS OF MELANOCORTIN PEPTIDES ON NEURAL MELANOCORTIN RECEPTORS

Melanocortins (MCs) have various physiological actions on the brain. T he recent cloning of neural MC receptors opened new avenues to study t he effects of these neuropeptides on the nervous system. Here we inves tigated the structure-activity relationships (SARs) of peptides derive d from adrenocorticotropic hormone (ACTH) with cloned MC3 and MC4 rece ptors in vitro and correlated these with central effects of MCs in viv o. Analysis of the effects of various MC peptides on cAMP accumulation in and binding to cells that expressed either the rat MC3 receptor or the human MC4 receptor demonstrated that ACTH-4-9-NH2 was the core se quence of ACTH able to activate these receptors. Furthermore, gamma-me lanocyte-stimulating hormone (MSH) displayed selectivity for the MC3 r eceptor, whereas [D-Phe(7)]ACTH-4-10 more efficiently activated the MC 4 receptor than the MC3 receptor. The activities of MC fragments that lacked the three carboxyl-terminal amino acids (residues 11-13) of ACT H-1-13 were much lower than that of alpha-MSH, for both receptors. Fur thermore, the three amino-terminal amino acids (residues 1-3) of alpha -MSH were more important for full activation of the MC4 receptor, comp ared with the MC3 receptor. The SAR for the MC4 receptor resembled tha t for the induction of excessive grooming behavior by MC peptides. The refore, we suggest that this behavioral response is mediated by MC4 re ceptors. The SAR for the MC3 receptor did not overlap with that for in vivo effects of MCs. ORG2766, an ACTH-4-9 analog that is very potent in an active avoidance task, did not activate, antagonize, or bind to the MC3 and MC4 receptors. This suggests the presence of still other M C receptors, in addition to the MC3 and MC4 receptors, in the brain. T hese data identify peptides with selectivity for either the MC3 recept or or the MC4 receptor, which may be used for development of novel MC receptor-specific ligands. Furthermore, this is the first report that discusses behavioral effects of MCs in light of data on cloned MC rece ptors.