%0 Journal Article %A R A Adan %A R D Cone %A J P Burbach %A W H Gispen %T Differential effects of melanocortin peptides on neural melanocortin receptors. %D 1994 %J Molecular Pharmacology %P 1182-1190 %V 46 %N 6 %X Melanocortins (MCs) have various physiological actions on the brain. The recent cloning of neural MC receptors opened new avenues to study the effects of these neuropeptides on the nervous system. Here we investigated the structure-activity relationships (SARs) of peptides derived from adrenocorticotropic hormone (ACTH) with cloned MC3 and MC4 receptors in vitro and correlated these with central effects of MCs in vivo. 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 sequence of ACTH able to activate these receptors. Furthermore, gamma-melanocyte-stimulating hormone (MSH) displayed selectivity for the MC3 receptor, whereas [D-Phe7]ACTH-4-10 more efficiently activated the MC4 receptor than the MC3 receptor. The activities of MC fragments that lacked the three carboxyl-terminal amino acids (residues 11-13) of ACTH-1-13 were much lower than that of alpha-MSH, for both receptors. Furthermore, the three amino-terminal amino acids (residues 1-3) of alpha-MSH were more important for full activation of the MC4 receptor, compared with the MC3 receptor. The SAR for the MC4 receptor resembled that for the induction of excessive grooming behavior by MC peptides. Therefore, we suggest that this behavioral response is mediated by MC4 receptors. 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 MC receptors, in addition to the MC3 and MC4 receptors, in the brain. These data identify peptides with selectivity for either the MC3 receptor 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 receptors. %U https://molpharm.aspetjournals.org/content/molpharm/46/6/1182.full.pdf