title: Allosteric modulation of G protein-coupled receptors: a pharmacological perspective.
abstract: G protein-coupled receptor (GPCR)-based drug discovery has traditionally focused on targeting the orthosteric site for the endogenous agonist. However, many GPCRs possess allosteric sites that offer enormous potential for greater selectivity in drug action. The complex behaviors ascribed to allosteric ligands also present challenges to those interested in preclinical lead discovery. These challenges include the need to detect and quantify various phenomena when screening for allosteric ligands, such as saturability of effect, probe dependence, differential effects on orthosteric ligand affinity vs. efficacy, system-dependent allosteric agonism, stimulus-bias (functional selectivity), and the potential existence of bitopic (hybrid orthosteric/allosteric) ligands. These issues are also critical when interpreting structure-function studies of allosteric GPCR modulators because mutations in receptor structure, either engineered or naturally occurring, can differentially affect not only modulator affinity, but also the nature, magnitude and direction of the allosteric effect on orthosteric ligand function. The ever-expanding array of allosteric modulators arising from both academic and industrial research also highlights the need for the development of a uniform approach to nomenclature of such compounds.
authors.affiliation: Monash Institute of Pharmaceutical Sciences & Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Keov
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
mesh_terms: D000494:Allosteric Regulation / Q000235:genetics; D000495:Allosteric Site / Q000235:genetics*; D055808:Drug Discovery; D009154:Mutation; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D043562:Receptors, G-Protein-Coupled