N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement

K. J. Gregory, E. J. Herman, A. J. Ramsey, Alexis Hammond, N. E. Byun, S. R. Stauffer, J. T. Manka, S. Jadhav, T. M. Bridges, C. D. Weaver, C. M. Niswender, T. Steckler, W. H. Drinkenburg, A. Ahnaou, H. Lavreysen, G. J. Macdonald, J. M. Bartolomé, C. Mackie, B. J. Hrupka, M. G. CaronT. L. Daigle, C. W. Lindsley, P. J. Conn, C. K. Jones

Research output: Contribution to journalArticle

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-difluorophen-yl)piperazin-1-yl)-2-((4- fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)438-457
Number of pages20
JournalJournal of Pharmacology and Experimental Therapeutics
Volume347
Issue number2
DOIs
StatePublished - Nov 2013
Externally publishedYes

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Metabotropic Glutamate 5 Receptor
N-Methylaspartate
Schizophrenia
Startle Reflex
Allosteric Site
Ionotropic Glutamate Receptors
Mitogen-Activated Protein Kinase 3
Apomorphine
Mitogen-Activated Protein Kinase 1
Amphetamine
Prefrontal Cortex
Psychotic Disorders
Antipsychotic Agents
Fear
Glutamic Acid
Electroencephalography
Therapeutics
Pharmacokinetics
Binding Sites
Phosphorylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement. / Gregory, K. J.; Herman, E. J.; Ramsey, A. J.; Hammond, Alexis; Byun, N. E.; Stauffer, S. R.; Manka, J. T.; Jadhav, S.; Bridges, T. M.; Weaver, C. D.; Niswender, C. M.; Steckler, T.; Drinkenburg, W. H.; Ahnaou, A.; Lavreysen, H.; Macdonald, G. J.; Bartolomé, J. M.; Mackie, C.; Hrupka, B. J.; Caron, M. G.; Daigle, T. L.; Lindsley, C. W.; Conn, P. J.; Jones, C. K.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 347, No. 2, 11.2013, p. 438-457.

Research output: Contribution to journalArticle

Gregory, KJ, Herman, EJ, Ramsey, AJ, Hammond, A, Byun, NE, Stauffer, SR, Manka, JT, Jadhav, S, Bridges, TM, Weaver, CD, Niswender, CM, Steckler, T, Drinkenburg, WH, Ahnaou, A, Lavreysen, H, Macdonald, GJ, Bartolomé, JM, Mackie, C, Hrupka, BJ, Caron, MG, Daigle, TL, Lindsley, CW, Conn, PJ & Jones, CK 2013, 'N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement', Journal of Pharmacology and Experimental Therapeutics, vol. 347, no. 2, pp. 438-457. https://doi.org/10.1124/jpet.113.206623
Gregory, K. J. ; Herman, E. J. ; Ramsey, A. J. ; Hammond, Alexis ; Byun, N. E. ; Stauffer, S. R. ; Manka, J. T. ; Jadhav, S. ; Bridges, T. M. ; Weaver, C. D. ; Niswender, C. M. ; Steckler, T. ; Drinkenburg, W. H. ; Ahnaou, A. ; Lavreysen, H. ; Macdonald, G. J. ; Bartolomé, J. M. ; Mackie, C. ; Hrupka, B. J. ; Caron, M. G. ; Daigle, T. L. ; Lindsley, C. W. ; Conn, P. J. ; Jones, C. K. / N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement. In: Journal of Pharmacology and Experimental Therapeutics. 2013 ; Vol. 347, No. 2. pp. 438-457.
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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-difluorophen-yl)piperazin-1-yl)-2-((4- fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca2+ 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.",
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AU - Gregory, K. J.

AU - Herman, E. J.

AU - Ramsey, A. J.

AU - Hammond, Alexis

AU - Byun, N. E.

AU - Stauffer, S. R.

AU - Manka, J. T.

AU - Jadhav, S.

AU - Bridges, T. M.

AU - Weaver, C. D.

AU - Niswender, C. M.

AU - Steckler, T.

AU - Drinkenburg, W. H.

AU - Ahnaou, A.

AU - Lavreysen, H.

AU - Macdonald, G. J.

AU - Bartolomé, J. M.

AU - Mackie, C.

AU - Hrupka, B. J.

AU - Caron, M. G.

AU - Daigle, T. L.

AU - Lindsley, C. W.

AU - Conn, P. J.

AU - Jones, C. K.

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