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Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents.
Rook, Jerri M; Xiang, Zixiu; Lv, Xiaohui; Ghoshal, Ayan; Dickerson, Jonathan W; Bridges, Thomas M; Johnson, Kari A; Foster, Daniel J; Gregory, Karen J; Vinson, Paige N; Thompson, Analisa D; Byun, Nellie; Collier, Rebekah L; Bubser, Michael; Nedelcovych, Michael T; Gould, Robert W; Stauffer, Shaun R; Daniels, J Scott; Niswender, Colleen M; Lavreysen, Hilde; Mackie, Claire; Conde-Ceide, Susana; Alcazar, Jesus; Bartolomé-Nebreda, José M; Macdonald, Gregor J; Talpos, John C; Steckler, Thomas; Jones, Carrie K; Lindsley, Craig W; Conn, P Jeffrey.
Affiliation
  • Rook JM; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Xiang Z; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Lv X; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Ghoshal A; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Dickerson JW; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Bridges TM; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Johnson KA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Foster DJ; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Gregory KJ; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australi
  • Vinson PN; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Thompson AD; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Byun N; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Collier RL; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Bubser M; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Nedelcovych MT; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Gould RW; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Stauffer SR; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Daniels JS; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Niswender CM; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Lavreysen H; Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • Mackie C; CREATe ADME/Tox, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • Conde-Ceide S; Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
  • Alcazar J; Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
  • Bartolomé-Nebreda JM; Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
  • Macdonald GJ; Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • Talpos JC; Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • Steckler T; Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • Jones CK; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Lindsley CW; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
  • Conn PJ; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: jeff.conn@vanderbilt.edu.
Neuron ; 86(4): 1029-1040, 2015 May 20.
Article in En | MEDLINE | ID: mdl-25937172
ABSTRACT
Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gαq-mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy. VIDEO ABSTRACT.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Antipsychotic Agents / Receptors, N-Methyl-D-Aspartate / Receptor, Metabotropic Glutamate 5 Limits: Animals / Humans / Male Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2015 Document type: Article Affiliation country:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Antipsychotic Agents / Receptors, N-Methyl-D-Aspartate / Receptor, Metabotropic Glutamate 5 Limits: Animals / Humans / Male Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2015 Document type: Article Affiliation country: