title: When simple agonism is not enough: emerging modalities of GPCR ligands.
abstract: Recent advances in G protein-coupled receptors have challenged traditional definitions of agonism, antagonism, affinity and efficacy. The discovery of agonist functional selectivity and receptor allosterism has meant researchers have an expanded canvas for designing and discovering novel drugs. Here we describe modes of agonism emerging from the discovery of functional selectivity and allosterism. We discuss the concept of ago-allosterism, where ligands can initiate signaling by themselves and influence the actions of another ligand at the same receptor. We introduce the concept of dualsteric ligands that consist of distinct elements which bind to each of the orthosteric and an allosteric domain on a single receptor to enhance subtype selectivity. Finally, the concept that efficacy should be defined by the activity of an endogenous ligand will be challenged by the discovery that some ligands act as 'super-agonists' in specific pathways or at certain receptor mutations.
authors.affiliation: Molecular Pharmacology Group, Neuroscience and Molecular Pharmacology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK. nicola.smith@bio.gla.ac.uk
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Smith
authors.forename: Kirstie A
authors.initials: KA
authors.lastname: Bennett
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D015195:Drug Design; D006801:Humans; D008024:Ligands; D058990:Molecular Targeted Therapy / Q000379:methods; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled