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

被引:72
作者
Haskell-Luevano, C
Rosenquist, Å
Souers, A
Khong, KC
Ellman, JA
Cone, RD
机构
[1] Oregon Hlth Sci Univ, Vollum Inst, Portland, OR 97201 USA
[2] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA
关键词
D O I
10.1021/jm990190s
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A library of 951 compounds based upon the beta-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 mu M. 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 mu M. The results of the library screening process are consistent with a hypothesis dating back to the 1980s proposing that a beta-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.
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页码:4380 / 4387
页数:8
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