title: N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement.
abstract: Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition of the N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors (NMDAR) induces a syndrome that recapitulates many of the symptoms observed in patients with schizophrenia. Selective activation of metabotropic glutamate receptor subtype 5 (mGlu5) may provide a novel therapeutic approach for treatment of symptoms associated with schizophrenia through facilitation of transmission through central glutamatergic circuits. Here, we describe the characterization of two novel N-aryl piperazine mGlu5 positive allosteric modulators (PAMs): 2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile (VU0364289) and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca(2+) mobilization and extracellular signal-regulated kinases 1 and 2 phosphorylation. Both PAMs displayed micromolar affinity for the common mGlu5 allosteric binding site and high selectivity for mGlu5. VU0364289 and DPFE possessed suitable pharmacokinetic properties for dosing in vivo and produced robust dose-related effects in reversing amphetamine-induced hyperlocomotion, a preclinical model predictive of antipsychotic-like activity. In addition, DPFE enhanced acquisition of contextual fear conditioning in rats and reversed behavioral deficits in a mouse model of NMDAR hypofunction. In contrast, DPFE had no effect on reversing apomorphine-induced disruptions of prepulse inhibition of the acoustic startle reflex. These mGlu5 PAMs also increased monoamine levels in the prefrontal cortex, enhanced performance in a hippocampal-mediated memory task, and elicited changes in electroencephalogram dynamics commensurate with procognitive effects. Collectively, these data support and extend the role for the development of novel mGlu5 PAMs for the treatment of psychosis and cognitive deficits observed in individuals with schizophrenia.
authors: Department of Pharmacology and Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee (K.J.G., E.J.H., A.S.H., N.E.B., S.R.S., J.T.M., S.J., T.M.B., C.D.W., C.M.N., C.W.L., P.J.C., C.K.J.); Drug Discovery Biology, MIPS, Monash University, Parkville, Victoria, Australia (K.J.G.); Department of Pharmacology and Toxicology, University of Toronto, Ontario, Canada (A.J.R.); Institute of Imaging and Science, Vanderbilt University (N.E.B.); Janssen Research & Development, Beerse, Belgium (T.S., W.H.D., A.A., H.L., G.J.M., C.M., B.J.H.); Janssen Research & Development, Toledo, Spain (J.M.B.); Department of Cell Biology, Duke University, Durham, North Carolina (M.G.C., T.L.D.); Department of Chemistry, Vanderbilt University Medical Center, Nashville, Tennessee (C.W.L.); and U.S. Department of Veterans Affairs, Nashville, Tennessee (C.K.J.).
authors: K J
authors: KJ
authors: Gregory
authors: E J
authors: EJ
authors: Herman
authors: A J
authors: AJ
authors: Ramsey
authors: A S
authors: AS
authors: Hammond
authors: N E
authors: NE
authors: Byun
authors: S R
authors: SR
authors: Stauffer
authors: J T
authors: JT
authors: Manka
authors: S
authors: S
authors: Jadhav
authors: T M
authors: TM
authors: Bridges
authors: C D
authors: CD
authors: Weaver
authors: C M
authors: CM
authors: Niswender
authors: T
authors: T
authors: Steckler
authors: W H
authors: WH
authors: Drinkenburg
authors: A
authors: A
authors: Ahnaou
authors: H
authors: H
authors: Lavreysen
authors: G J
authors: GJ
authors: Macdonald
authors: J M
authors: JM
authors: Bartolomé
authors: C
authors: C
authors: Mackie
authors: B J
authors: BJ
authors: Hrupka
authors: M G
authors: MG
authors: Caron
authors: T L
authors: TL
authors: Daigle
authors: C W
authors: CW
authors: Lindsley
authors: P J
authors: PJ
authors: Conn
authors: C K
authors: CK
authors: Jones
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D006948:Hyperkinesis / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D018697:Nootropic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D014162:Transfection
chemical_list: C585148:1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone; C585147:2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile; D014150:Antipsychotic Agents; C578937:Grm5 protein, rat; C409466:NR1 NMDA receptor; D018697:Nootropic Agents; D010879:Piperazines; D064529:Receptor, Metabotropic Glutamate 5; D016194:Receptors, N-Methyl-D-Aspartate
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