Two small molecule agonists of glucagon-like peptide-1 receptor modulate the receptor activation response differently

Biochem Biophys Res Commun. 2012 Jan 6;417(1):558-63. doi: 10.1016/j.bbrc.2011.12.004. Epub 2011 Dec 8.


The glucagon-like peptide-1 receptor (GLP-1R) is a target for type 2 diabetes treatment. Due to the inconvenience of peptide therapeutics, small-molecule GLP-1R agonists have been studied. Compound 2 (6,7-dichloro-2-methylsulfonyl-2-N-tert-butylaminoquinoxaline) and compound B (4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine) have been described as small molecule, ago-allosteric modulators of GLP-1R. However, their modes of action at the GLP-1R have not been elucidated. Thus, in this study, we compared the mechanisms of action between these two compounds. When compound 2 was treated with endogenous or exogenous peptide agonists (GLP-1 and exenatide) or fragments of peptide agonists (GLP-1(9-36), Ex3, Ex4, and Ex5), the response curve of these peptide agonists shifted left without a change in maximum efficacy. In contrast, compound B potentiated the response and increased maximum efficacy. However, N-terminal truncated orthosteric antagonists including Ex7, Ex9, and Ex10, augmented the response of compound 2 at the GLP-1R but did not alter compound B activity. Intriguingly, when we co-treated compound 2 with compound B in CHO cells expressing full-length hGLP-1R or N-terminal extracellular domain-truncated GLP-1R, the activation of both types of receptors increased additively, implying that the N-terminus of the receptor is not involved in the modulation by compound agonists. We confirmed that these two compounds increased calcium influx by different patterns in CHO cells expressing GLP-1R. Taken together, our findings suggest that compounds 2 and B have different modes of action to activate GLP-1R. Further study to identify the putative binding sites will help in the discovery of orally available GLP-1R agonists.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Calcium / metabolism*
  • Cricetinae
  • Exenatide
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Peptides / pharmacology
  • Pyrimidines / pharmacology*
  • Quinoxalines / pharmacology*
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / biosynthesis
  • Sulfones / pharmacology*
  • Venoms / pharmacology


  • 3-(tert-butylamino)-6,7-dichloro-2-(methylsulfonyl)quinoxaline
  • 4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Peptides
  • Pyrimidines
  • Quinoxalines
  • Receptors, Glucagon
  • Sulfones
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide
  • Calcium