Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents.
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.
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Jerri M
JM
Rook
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Zixiu
Z
Xiang
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Xiaohui
X
Lv
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Ayan
A
Ghoshal
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Jonathan W
JW
Dickerson
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Thomas M
TM
Bridges
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Kari A
KA
Johnson
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Daniel J
DJ
Foster
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, Australia.
Karen J
KJ
Gregory
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Paige N
PN
Vinson
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Analisa D
AD
Thompson
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Nellie
N
Byun
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Rebekah L
RL
Collier
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Michael
M
Bubser
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Michael T
MT
Nedelcovych
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Robert W
RW
Gould
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Shaun R
SR
Stauffer
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
J Scott
JS
Daniels
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Colleen M
CM
Niswender
Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Hilde
H
Lavreysen
CREATe ADME/Tox, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Claire
C
Mackie
Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
Susana
S
Conde-Ceide
Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
Jesus
J
Alcazar
Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
José M
JM
Bartolomé-Nebreda
Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Gregor J
GJ
Macdonald
Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
John C
JC
Talpos
Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Thomas
T
Steckler
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Carrie K
CK
Jones
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Craig W
CW
Lindsley
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.
P Jeffrey
PJ
Conn
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
D014150:Antipsychotic Agents; D064529:Receptor, Metabotropic Glutamate 5; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid