Potent and selective agonists of α-melanotropin (αMSH) action at human melanocortin receptor 5; linear analogs of α-melanotropin

α-Melanotropin, Ac-Ser1-Tyr-Ser-Met-Glu-His6-Phe7-Arg8-Trp9-Gly-Lys-Pro-Val13-NH21, is a non-selective endogenous agonist for the melanocortin receptor 5; the receptor present in various peripheral tissues and in the brain, cortex and cerebellum. Most of the synthetic analogs of αMSH, including a broadly used and more potent the NDP-αMSH peptide, Ac-Ser1-Tyr-Ser-Nle4-Glu-His6-D-Phe7-Arg8-Trp9-Gly-Lys-Pro-Val13-NH2, are also not particularly selective for MC5R. To elucidate physiological functions of the melanocortin receptor 5 in rodents and humans, the receptor subtype selective research tools are needed. We report herein syntheses and pharmacological evaluation in vitro of several analogs of NDP-αMSH which are highly potent and specific agonists for the human MC5R. The new linear peptides, of structures and solubility properties similar to those of the endogenous ligand αMSH, are exemplified by compound 7, Ac-Ser1-Tyr-Ser-Met-Glu-Oic6-D-4,4′-Bip7-Pip8-Trp9-Gly-Lys-Pro-Val13-NH2 (Oic: octahydroindole-2-COOH, 4,4′-Bip: 4,4′-biphenylalanine, Pip: pipecolic acid), shortly NODBP-αMSH, which has an IC50 = 0.74 nM (binding assay) and EC50 = 0.41 (cAMP production assay) at hMC5R nM and greater than 3500-fold selectivity with respect to the melanocortin receptors 1b, 3 and 4. A shorter peptide derived from NODBP-αMSH: Ac-Nle-Glu-Oic6-D-4,4′-Bip7-Pip8-Trp9 -NH2 (17) was measured to be an agonist only 10-fold less potent at hMC5R than the full length parent peptide. In the structure of this smaller analog, the Nle-Glu-Oic6-D-4,4′-Bip7-Pip8 segment was found to be critical for high agonist potency, while the C-terminal Trp9 residue was shown to be required for high hMC5R selectivity versus hMC1b,3,4R.