期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 390, 期 3, 页码 557-563出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2009.10.004
关键词
GPR40; Antagonist; Type 2 diabetes; Homology modeling; Virtual screening; Sulfonamide
资金
- National High Technology Research and Development Program of China (863 Program) [2007AA02Z301, 2006AA02Z336]
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences [07G603L056]
The free fatty acid receptor, GPR40, is implicated in the pathophysiology of type 2 diabetes, and is a new potential drug target for the treatment of type 2 diabetes. Its antagonist is thought to be not only a useful chemical probe for further exploring the function of GPR40 but also a lead structure for drug development. With virtual screening based on a homology model followed by a cell-based calcium mobilization assay, we found that sulfonamides are a new class of small organic antagonists for GPR40. One of the compounds, DC260126, dose-dependently inhibited GPR40-mediated Ca2+ elevations stimulated by linoleic acid, oleic acid, palmitoleic acid and lauric acid (IC50: 6.28 +/- 1.14, 5.96 +/- 1.12, 7.07 +/- 1.42, 4.58 +/- 1.14 mu M, respectively), reduced GTP-loading and ERK1/2 phosphorylation stimulated by linoleic acid in GPR40-CHO cells, suppressed palmitic acid potentiated glucose-stimulated insulin secretion, and negatively regulated GPR40 mRNA expression induced by oleic acid in Min6 cells. (C) 2009 Elsevier Inc. All rights reserved.
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