Compounds that activate the mouse melanocortin-1 receptor identified by screening a small molecule library based upon the β-turn

Abstract

A library of 951 compounds based upon the β-turn motif were examined for their ability to stimulate the melanocortin-1 receptor. From this screening process, we have identified two compounds possessing low micromolar agonist activity at the mMC1R. The compound EL1 with racemic Nal(2') in the i + 1 position, DPro in the i + 2 position, and Trp in the i + 3 position possesses an EC50 of 42.5 ± 6.9 μM. Compound EL2 with Trp in the i + 1 position, DLys in the i + 2 position, and Phe in the i + 3 position possesses an EC50 value of 63.4 ± 26.9 μM. The results of the library screening process are consistent with a hypothesis dating back to the 1980s proposing that a β-turn conformation involving the melanocortin 'Phe-Arg-Trp' core amino acids provides the key recognition element. Additionally, these compounds represent the first nonpeptidic heterocyclic molecules reported to date that are able to activate the MC1R, a melanocyte receptor involved in skin pigmentation and animal coat coloration.