TY - JOUR T1 - Allosteric Modulation of Endogenous Metabolites as an Avenue for Drug Discovery JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.079319 SP - mol.112.079319 AU - Denise Wootten AU - Emilia E Savage AU - Celine Valant AU - Lauren T May AU - Kyle W Sloop AU - James Ficorilli AU - Aaron D Showalter AU - Francis S Willard AU - Arthur Christopoulos AU - Patrick Sexton Y1 - 2012/01/01 UR - http://molpharm.aspetjournals.org/content/early/2012/05/10/mol.112.079319.abstract N2 - G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and a key drug target class. Recently, allosteric drugs that can co-bind with, and modulate the activity of, the endogenous ligand(s)for the receptor have become a major focus of the pharmaceutical and biotechnology industry for the development of novel GPCR therapeutics. This class of drugs has distinct properties when compared to drugs targeting the endogenous(orthosteric)ligand binding site that include the ability to sculpt cellular signalling, and to respond differently in the presence of discrete orthosteric ligands; a behaviour termed "probe dependence". Here, using cell signalling assays combined with ex vivo and in vivo studies of insulin secretion, we demonstrate that allosteric ligands can cause marked potentiation of previously "inert" metabolic products of neurotransmitters and peptide hormones, a novel consequence of the phenomenon of probe dependence. Indeed, at the muscarinic M2 receptor and glucagon-like peptide-1 receptor, allosteric potentiation of the metabolites, choline and GLP-1(9-36)NH2, respectively, was ~100-fold and up to 200-fold greater than that seen with the physiological signalling molecules acetylcholine and GLP-1(7-36)NH2. Modulation of GLP-1(9-36)NH2 was also demonstrated in ex vivo and in vivo assays of insulin secretion.This work opens up new avenues for allosteric drug discovery by directly targeting modulation of metabolites, but it also identifies a behaviour that could contribute to unexpected clinical outcomes if interaction of allosteric drugs with metabolites is not part of their preclinical assessment. ER -