Design of cyclic peptides with agonist activity at melanocortin receptor-4

A series of cyclic pentapeptides, c(His-d-Phe-Arg-Trp-Z) (Z = ω-amino acid), were prepared and biologically evaluated. The effects of increasing alkyl chain length of ω-amino acid on the functional activities and the receptor binding affinities for human melanocortin receptors (hMC-Rs) were studied. Compound 2was an agonist for hMC-4R with an EC50 value of 15.4 nM, which was 4.7 times more potent than that of α-MSH. Compound 2 also showed a 4.3-fold higher hMC-4R selectivity over hMC-1R, thus providing us with information concerning size and chemical structure of the lactam ring for the development of the agonist with hMC-4R selectivity.