title: Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders.
abstract: Novel allosteric modulators of G protein-coupled receptors (GPCRs) are providing fundamental advances in the development of GPCR ligands with high subtype selectivity and novel modes of efficacy that have not been possible with traditional approaches. As new allosteric modulators are advancing as drug candidates, we are developing an increased understanding of the major advantages and broad range of activities that can be achieved with these agents through selective modulation of specific signalling pathways, differential effects on GPCR homodimers versus heterodimers, and other properties. This understanding creates exciting opportunities, as well as unique challenges, in the optimization of novel therapeutic agents for disorders of the central nervous system.
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 1215D LH, USA.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 1215D LH, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Meiler
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 1215D LH, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002491:Central Nervous System Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods / Q000639:trends*; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D002491:Central Nervous System Agents; D043562:Receptors, G-Protein-Coupled