MOLECULAR PHARMACOLOGY OF NEURAL MELANOCORTIN RECEPTORS

The cloning of melanocortin receptors opened new avenues to identify s elective ligands for this receptor family. gamma-MSH was characterized as a melanocortin-3 receptor selective agonist. [D-Arg(8)]ACTH-(4-10) and [Pro (8,10),Gly(9)]ACTH-(4-10) were characterized as melanocortin -4 receptor antagonists. The application of these ligands in vivo reve aled that melanocortin-4 receptors mediate melanocortin-induced groomi ng behaviour in the rat. Since we still lack potent and selective mela nocortin receptor ligands, we performed homology modelling and site di rected mutagenesis of the melanocortin-4 receptor, in order to underst and how melanocortins bind melanocortin receptors. A histidine at posi tion 260 in the melanocortin-4 receptor is important for normal recept or function. However this residue is not forming a salt bridge with a glutamate at position 92 to keep the receptor in an inactive conformat ion, nor with the glutamate in the melanocortin peptides as had been s uggested before.