Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: implications for drug screening

Cassandra Koole, Denise Wootten, John Simms, Celine Valant, Rohan Sridhar, Owen L Woodman, Laurence J Miller, Roger J Summers, Arthur Christopoulos, Patrick M Sexton

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of insulin secretion and a major therapeutic target for treatment of diabetes. However, GLP-1 receptor function is complex, with multiple endogenous peptides that can interact with the receptor, including full-length (1-37) and truncated (7-37) forms of GLP-1 that can each exist in an amidated form and the related peptide oxyntomodulin. We have investigated two GLP-1 receptor allosteric modulators, Novo Nordisk compound 2 (6,7-dichloro2-methylsulfonyl-3-tert-butylaminoquinoxaline) and quercetin, and their ability to modify binding and signaling (cAMP formation, intracellular Ca(2+) mobilization, and extracellular signal-regulated kinase 1/2 phosphorylation) of each of the naturally occurring endogenous peptide agonists, as well as the clinically used peptide mimetic exendin-4. We identified and quantified stimulus bias across multiple endogenous peptides, with response profiles for truncated GLP-1 peptides distinct from those of either the full-length GLP-1 peptides or oxyntomodulin, the first demonstration of such behavior at the GLP-1 receptor. Compound 2 selectively augmented cAMP signaling but did so in a peptide-agonist dependent manner having greatest effect on oxyntomodulin, weaker effect on truncated GLP-1 peptides, and negligible effect on other peptide responses; these effects were principally driven by parallel changes in peptide agonist affinity. In contrast, quercetin selectively modulated calcium signaling but with effects only on truncated GLP-1 peptides or exendin and not oxyntomodulin or full-length peptides. These data have significant implications for how GLP-1 receptor targeted drugs are screened and developed, whereas the allosterically driven, agonist-selective, stimulus bias highlights the potential for distinct clinical efficacy depending on the properties of individual drugs.

Original languageEnglish
Pages (from-to)456-465
Number of pages10
JournalMolecular Pharmacology
Volume78
Issue number3
DOIs
Publication statusPublished - Sep 2010

Keywords

  • Animals
  • Cricetinae
  • Drug Evaluation, Preclinical
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Ligands
  • Mitogen-Activated Protein Kinase 3
  • Oxyntomodulin
  • Peptides
  • Receptors, Glucagon
  • Signal Transduction
  • Venoms
  • Journal Article
  • Research Support, Non-U.S. Gov't

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