The 1,4-benzodiazepine-2,5-dione small molecule template results in melanocortin receptor agonists with nanomolar potencies

Christine G. Joseph, Krista R. Wilson, Michael S. Wood, Nicholas B. Sorenson, Dong V. Phan, Zhimin Xiang, Rachel M. Witek, Carrie Haskell-Luevano

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

The melanocortin system consists of five seven-transmembrane spanning G-protein coupled receptors (MC1-5) that are stimulated by endogenous agonists and antagonized by the only two known endogenous antagonists of GPCRs, agouti and agouti-related protein (AGRP). These receptors have been associated with many physiological functions, including the involvement of the MC4R in feeding behavior and energy homeostasis, making this system an attractive target for the treatment of obesity. Small-molecule mimetics of endogenous ligands may result in the development of compounds with properties more suitable for use as therapeutic agents. The research presented herein involves the synthesis and analysis of 12 melanocortin receptor agonists using the 1,4-benzodiazepine-2,5- dione template and is the first report of these derivatives as melanocortin receptor agonists. Structure-activity relationship studies using this privileged structure template has resulted in molecules with molecular weights around 400 that possess nanomolar agonist potency at the melanocortin receptors examined in this study.

Original languageEnglish (US)
Pages (from-to)1423-1431
Number of pages9
JournalJournal of medicinal chemistry
Volume51
Issue number5
DOIs
StatePublished - Mar 13 2008

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