title: Neurobiological Insights from mGlu Receptor Allosteric Modulation.
abstract: Allosteric modulation of metabotropic glutamate (mGlu) receptors offers a promising pharmacological approach to normalize neural circuit dysfunction associated with various psychiatric and neurological disorders. As mGlu receptor allosteric modulators progress through discovery and clinical development, both technical advances and novel tool compounds are providing opportunities to better understand mGlu receptor pharmacology and neurobiology. Recent advances in structural biology are elucidating the structural determinants of mGlu receptor-negative allosteric modulation and supplying the means to resolve active, allosteric modulator-bound mGlu receptors. The discovery and characterization of allosteric modulators with novel pharmacological profiles is uncovering the biological significance of their intrinsic agonist activity, biased mGlu receptor modulation, and novel mGlu receptor heterodimers. The development and exploitation of optogenetic and optopharmacological tools is permitting a refined spatial and temporal understanding of both mGlu receptor functions and their allosteric modulation in intact brain circuits. Together, these lines of research promise to provide a more refined understanding of mGlu receptors and their allosteric modulation that will inform the development of mGlu receptor allosteric modulators as neurotherapeutics in the years to come.
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee (Drs O'Brien and Conn).
authors.forename: Daniel E
authors.initials: DE
authors.lastname: O'Brien
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee (Drs O'Brien and Conn). jeff.conn@vanderbilt.edu.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D062308:Optogenetics; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate
keywords: GPCR biased signaling; GPCR heterodimers; allosteric modulators; brain disorders; mGlu receptor