@article {Koolemol.110.065664, author = {Cassandra Koole and Denise Wootten and John Simms and Celine Valant and Rohan Sridhar and Owen L Woodman and Laurence J Miller and Roger J. Summers and Arthur Christopoulos and Patrick Sexton}, title = {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}, elocation-id = {mol.110.065664}, year = {2010}, doi = {10.1124/mol.110.065664}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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 and quercetin, and their ability to modify binding and signalling (cAMP formation, intracellular Ca2+ mobilisation and ERK1/2 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 behaviour at the GLP-1 receptor. Compound 2 selectively augmented cAMP signalling 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 signalling 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, while the allosterically driven, agonist-selective, stimulus bias highlights the potential for distinct clinical efficacy depending on the properties of individual drugs.The American Society for Pharmacology and Experimental Therapeutics}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2010/06/14/mol.110.065664}, eprint = {https://molpharm.aspetjournals.org/content/early/2010/06/14/mol.110.065664.full.pdf}, journal = {Molecular Pharmacology} }