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Updated: Jun 19, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
A novel class of antagonists for the FFAs receptor GPR40
Hui Hu1, Ling Yan He, Zhen Gong
1Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhang Jiang Hi-Tech Park, Shanghai 201203, China.
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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