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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Calcium Signaling / drug effects
  • Cricetulus
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Glucose / metabolism
  • HEK293 Cells
  • High-Throughput Screening Assays
  • Humans
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Mice
  • Molecular Structure
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / drug effects*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Reproducibility of Results
  • Second Messenger Systems / drug effects
  • Small Molecule Libraries*
  • Structure-Activity Relationship
  • Time Factors
  • Tissue Culture Techniques
  • Transfection


  • GPR119 protein, human
  • Gpr119 protein, mouse
  • Hypoglycemic Agents
  • Insulin
  • Receptors, G-Protein-Coupled
  • Small Molecule Libraries
  • Cyclic AMP
  • Glucose