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

130 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 Ca2+ 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 (US)
Pages (from-to)456-465
Number of pages10
JournalMolecular Pharmacology
Volume78
Issue number3
DOIs
StatePublished - 2010

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Preclinical Drug Evaluations
Ligands
Peptides
Oxyntomodulin
Glucagon-Like Peptide 1
Quercetin
Glucagon-Like Peptide-1 Receptor
Calcium Signaling
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

Cite this

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

In: Molecular Pharmacology, Vol. 78, No. 3, 2010, p. 456-465.

Research output: Contribution to journalArticle

Koole, Cassandra ; Wootten, Denise ; Simms, John ; Valant, Celine ; Sridhar, Rohan ; Woodman, Owen L. ; Miller, Laurence J ; Summers, Roger J. ; Christopoulos, Arthur ; Sexton, Patrick M. / 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. In: Molecular Pharmacology. 2010 ; Vol. 78, No. 3. pp. 456-465.
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