کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1932823 | 1050595 | 2009 | 7 صفحه PDF | دانلود رایگان |
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 μM, 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.
Journal: Biochemical and Biophysical Research Communications - Volume 390, Issue 3, 18 December 2009, Pages 557–563