Agonists and/or modulators of the glucagon-like peptide-1 receptor (GLP-1R) are a major target for the treatment and management of type II diabetes; however, the approved drugs (exenatide and liraglutide) do not provide ideal therapeutics because of their peptidic nature, thus the search for small-molecule, orally active compounds that modulate GLP-1R. Wootten et al., after demonstrating the allosteric modulation of GLP-1R by the flavonoid quercetin, investigated the structure-activity relationship (SAR) of quercetin as a modulator of GLP-1R signaling. The flavonoid SAR revealed a chemical series of hydroxyflavonoids that selectively augmented calcium signaling in a peptide agonist-specific manner and identified the crucial roles of the 3-hydroxyl group and multiple substituent hydroxyl groups of the phenyl ring for positive allosteric modulator activity. Although flavonoids are unlikely to be good starting structures for development, the flavonol scaffold may provide a useful tool by which to study GLP-1R modulation and probe allosteric interactions at this receptor. The flavonoid SAR described in this article may aid in drug discovery efforts in the development of viable therapeutics for the management of type II diabetes.
See article at J Pharmacol Exp Ther 2011, 336:540–550.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics