Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp9 in molecular recognition

Abstract

α-Melanocyte stimulating hormone (αMSH), Ac-Ser¹-Tyr²-Ser³-Met⁴-Glu⁵-His⁶-Phe⁷-Arg⁸-Trp⁹-Gly¹⁰-Lys¹¹-Pro¹²-Val¹³-NH₂, 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-Ser¹-Tyr²-Ser³-Nle⁴-Glu⁵-His⁶-D-Phe⁷-Arg⁸-Trp⁹-Gly¹⁰-Lys¹¹-Pro¹²-Val¹³-NH₂, 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 Trp⁹ of NDP-αMSH in interactions with hMC1bR. Analogs of NDP-αMSH with various amino acids in place of Trp⁹ 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 (EC₅₀ = 0.5–5 nM) and receptor subtype selectivity greater than 2000-fold versus hMC3-5R. The Trp⁹ 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