A novel class of antagonists for the FFAs receptor GPR40

被引：57

作者：

Hu, Hui ^{[1
]}

He, Ling Yan ^{[1
]}

Gong, Zhen ^{[1
]}

Li, Ning ^{[1
]}

Lu, Yi Na ^{[1
]}

Zhai, Qi Wei ^{[2
]}

Liu, Hong ^{[1
]}

Jiang, Hua Liang ^{[1
]}

Zhu, Wei Liang ^{[1
]}

Wang, He Yao ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Nutr & Metab, Shanghai 200031, Peoples R China

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2009年 / 390卷 / 03期

基金：

国家高技术研究发展计划(863计划);

关键词：

GPR40; Antagonist; Type; 2; diabetes; Homology modeling; Virtual screening; Sulfonamide; PANCREATIC BETA-CELLS; STIMULATED INSULIN-SECRETION; FREE FATTY-ACIDS; IN-VIVO; IDENTIFICATION; LIPOTOXICITY; MOLECULES; DISCOVERY; PROGRAMS; DOCKING;

D O I：

10.1016/j.bbrc.2009.10.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：557 / 563

页数：7

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