PT  - JOURNAL ARTICLE
AU  - Cassandra Koole
AU  - Denise Wootten
AU  - John Simms
AU  - Celine Valant
AU  - Rohan Sridhar
AU  - Owen L. Woodman
AU  - Laurence J. Miller
AU  - Roger J. Summers
AU  - Arthur Christopoulos
AU  - Patrick M. Sexton
TI  - 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
AID  - 10.1124/mol.110.065664
DP  - 2010 Sep 01
TA  - Molecular Pharmacology
PG  - 456--465
VI  - 78
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/78/3/456.short
4100  - http://molpharm.aspetjournals.org/content/78/3/456.full
SO  - Mol Pharmacol2010 Sep 01; 78
AB  - 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.