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Acta Pharmacol Sin. 2014 Apr;35(4):540-8. doi: 10.1038/aps.2014.8. Epub 2014 Mar 31.

Discovery and characterization of novel small molecule agonists of G protein-coupled receptor 119.

Author information

1
Laboratory of Receptor-based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
2
CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3
1] Laboratory of Receptor-based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China [2] CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Abstract

AIM:

GPR119 is a G protein-coupled receptor (GPCR) that is highly expressed in pancreatic β-cells and intestinal L-cells and facilitates glucose-stimulated insulin secretion (GSIS). GPR119 may represent a novel target for the treatment of metabolic disorders. Here, we sought to identify novel small-molecule GPR119 agonists.

METHODS:

A cell-based high-throughput screening assay was established using HEK293 cells stably expressing GPR119 and pCRE-luc reporter plasmid (HEK293/GPR119/pCRE-luc). A compound library composed of 1440 compounds was screened. Mouse β-cell line MIN-6 and isolated mouse islets were used to evaluate the effects of candidate compounds on GSIS in vitro.

RESULTS:

Three compounds with novel structures (ZSY-04, -06, and -13) were found to activate GPR119-mediated signaling and to induce GPR119 desensitization. The EC50 values of ZSY-04, -06, and -13 in stimulating intracellular cAMP accumulation in HEK293/GPR119 cells were 2.758, 3.046, and 0.778 μmol/L, respectively. Furthermore, all three compounds displayed high selectivity for GPR119, and did not activate other 9 GPCRs tested. Moreover, all three compounds significantly increased GSIS in both MIN-6 mouse β-cells and isolated mouse islets at concentration of 10 μmol/L.

CONCLUSION:

Three novel small-molecule GPR119 agonists (ZSY-04, -06, and -13) with high receptor selectivity and capacity to induce GSIS in vitro were discovered. These compounds are potential candidates to be structurally optimized into drugs for the treatment of type 2 diabetes.

PMID:
24681896
PMCID:
PMC4813729
DOI:
10.1038/aps.2014.8
[Indexed for MEDLINE]
Free PMC Article

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