Compounds that activate the mouse melanocortin-1 receptor identified by screening a small molecule library based upon the beta-turn.
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 EC(50) of 42.5 +/- 6.9 microM. Compound EL2 with Trp in the i + 1 position, DLys in the i + 2 position, and Phe in the i + 3 position possesses an EC(50) value of 63.4 +/- 26.9 microM. 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.
Haskell-Luevano
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C
Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201,USA. Carrie@cop.ufl.edu
Rosenquist
A
A
Souers
A
A
Khong
K C
KC
Ellman
J A
JA
Cone
R D
RD
D000818:Animals; D002478:Cells, Cultured; D015195:Drug Design; D008024:Ligands; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D018043:Receptors, Corticotropin / Q000819:agonists / Q000096:biosynthesis / Q000737:chemistry*; D044101:Receptors, Melanocortin; D013329:Structure-Activity Relationship
D008024:Ligands; D009842:Oligopeptides; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin