title: Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity.
abstract: BACKGROUND
  Metabotropic glutamate receptor subtype 5 (mGlu5) activators have emerged as a novel approach to the treatment of schizophrenia. Positive allosteric modulators (PAMs) of mGlu5 have generated tremendous excitement and fueled major drug discovery efforts. Although mGlu5 PAMs have robust efficacy in preclinical models of schizophrenia, preliminary reports suggest that these compounds may induce seizure activity. Prototypical mGlu5 PAMs do not activate mGlu5 directly but selectively potentiate activation of mGlu5 by glutamate. This mechanism may be critical to maintaining normal activity-dependence of mGlu5 activation and achieving optimal in vivo effects.
  
  
  METHODS
  Using specially engineered mGlu5 cell lines incorporating point mutations within the allosteric and orthosteric binding sites, as well as brain slice electrophysiology and in vivo electroencephalography and behavioral pharmacology, we found that some mGlu5 PAMs have intrinsic allosteric agonist activity in the absence of glutamate.
  
  
  RESULTS
  Both in vitro mutagenesis and in vivo pharmacology studies demonstrate that VU0422465 is an agonist PAM that induces epileptiform activity and behavioral convulsions in rodents. In contrast, VU0361747, an mGlu5 PAMs optimized to eliminate allosteric agonist activity, has robust in vivo efficacy and does not induce adverse effects at doses that yield high brain concentrations.
  
  
  CONCLUSIONS
  Loss of the absolute dependence of mGlu5 PAMs on glutamate release for their activity can lead to severe adverse effects. The finding that closely related mGlu5 PAMs can differ in their intrinsic agonist activity provides critical new insights that is essential for advancing these molecules through clinical development for treatment of schizophrenia.
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232-0697, USA.
authors.forename: Jerri M
authors.initials: JM
authors.lastname: Rook
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Noetzel
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Pouliot
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: Paige N
authors.initials: PN
authors.lastname: Vinson
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhou
authors.forename: Rocco D
authors.initials: RD
authors.lastname: Gogliotti
authors.forename: Jason T
authors.initials: JT
authors.lastname: Manka
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Gregory
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.forename: F Edward
authors.initials: FE
authors.lastname: Dudek
authors.forename: Zixiu
authors.initials: Z
authors.lastname: Xiang
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010848:Picolinic Acids / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists* / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced
chemical_list: C588029:(6-((3-fluorophenyl)ethynyl)pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone; C588028:5-((3-fluorophenyl)ethynyl)-N-(3-hydroxy-3-methylbutan-2-yl)picolinamide; D018690:Excitatory Amino Acid Agonists; D010848:Picolinic Acids; D064529:Receptor, Metabotropic Glutamate 5; D009536:Niacinamide