2. Academic Validation
  3. A novel class of antagonists for the FFAs receptor GPR40

A novel class of antagonists for the FFAs receptor GPR40

  • Biochem Biophys Res Commun. 2009 Dec 18;390(3):557-63. doi: 10.1016/j.bbrc.2009.10.004.
Hui Hu 1,  Ling Yan He,  Zhen Gong,  Ning Li,  Yi Na Lu,  Qi Wei Zhai,  Hong Liu,  Hua Liang Jiang,  Wei Liang Zhu,  He Yao Wang
Affiliations

Affiliation

  • 1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhang Jiang Hi-Tech Park, Shanghai 201203, China.
PMID: 19818732 DOI: 10.1016/j.bbrc.2009.10.004
Abstract

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 Ca(2+) elevations stimulated by linoleic acid, oleic acid, palmitoleic acid and lauric acid (IC(50): 6.28+/-1.14, 5.96+/-1.12, 7.07+/-1.42, 4.58+/-1.14 microM, 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.

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