Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp 9 in molecular recognition

α‐Melanocyte stimulating hormone (αMSH), Ac‐Ser 1 ‐Tyr 2 ‐Ser 3 ‐Met 4 ‐Glu 5 ‐His 6 ‐Phe 7 ‐Arg 8 ‐Trp 9 ‐Gly 10 ‐Lys 11 ‐Pro 12 ‐Val 13 ‐NH 2 , is an endogenous agonist for the melanocortin receptor 1 (MC1R), the receptor found in the skin, several types of immune cells, and other peripheral sites. Three‐dimensional models of complexes of this receptor with αMSH and its synthetic analog NDP‐αMSH, Ac‐Ser 1 ‐Tyr 2 ‐Ser 3 ‐Nle 4 ‐Glu 5 ‐His 6 ‐ D ‐Phe 7 ‐Arg 8 ‐Trp 9 ‐Gly 10 ‐Lys 11 ‐Pro 12 ‐Val 13 ‐NH 2 , have been previously proposed. In those models, the 6–9 segment of the ligand was considered essential for the ligand‐receptor interactions. In this study, we probed the role of Trp 9 of NDP‐αMSH in interactions with hMC1bR. Analogs of NDP‐αMSH with various amino acids in place of Trp 9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4, and 5 (hMC1b,3‐5R). Several new compounds displayed high agonist potency at hMC1bR (EC 50 = 0.5–5 n M ) and receptor subtype selectivity greater than 2000‐fold versus hMC3‐5R. The Trp 9 residue of NDP‐αMSH was determined to be not essential for molecular recognition at hMC1bR. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 401–408, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com