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Research ArticleDrug Discovery and Translational Medicine

Positive Allosteric Modulation of the Muscarinic M1 Receptor Improves Efficacy of Antipsychotics in Mouse Glutamatergic Deficit Models of Behavior

Kwok H. C. Choy, David M. Shackleford, Daniel T. Malone, Shailesh N. Mistry, Rahul T. Patil, Peter J. Scammells, Christopher J. Langmead, Christos Pantelis, Patrick M. Sexton, Johnathan R. Lane and Arthur Christopoulos
Journal of Pharmacology and Experimental Therapeutics November 2016, 359 (2) 354-365; DOI: https://doi.org/10.1124/jpet.116.235788
Kwok H. C. Choy
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
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David M. Shackleford
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
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Daniel T. Malone
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
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Shailesh N. Mistry
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
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Rahul T. Patil
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
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Peter J. Scammells
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
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Christopher J. Langmead
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
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Christos Pantelis
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
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Patrick M. Sexton
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
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Johnathan R. Lane
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
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Arthur Christopoulos
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
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Abstract

Current antipsychotics are effective in treating the positive symptoms associated with schizophrenia, but they remain suboptimal in targeting cognitive dysfunction. Recent studies have suggested that positive allosteric modulation of the M1 muscarinic acetylcholine receptor (mAChR) may provide a novel means of improving cognition. However, very little is known about the potential of combination therapies in extending coverage across schizophrenic symptom domains. This study investigated the effect of the M1 mAChR positive allosteric modulator BQCA [1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid], alone or in combination with haloperidol (a first-generation antipsychotic), clozapine (a second-generation atypical antipsychotic), or aripiprazole (a third-generation atypical antipsychotic), in reversing deficits in sensorimotor gating and spatial memory induced by the N-methyl-d-aspartate receptor antagonist, MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]. Sensorimotor gating and spatial memory induction are two models that represent aspects of schizophrenia modeled in rodents. In prepulse inhibition (an operational measure of sensorimotor gating), BQCA alone had minimal effects but exhibited different levels of efficacy in reversing MK-801–induced prepulse inhibition disruptions when combined with a subeffective dose of each of the three (currently prescribed) antipsychotics. Furthermore, the combined effect of BQCA and clozapine was absent in M1−/− mice. Interestingly, although BQCA alone had no effect in reversing MK-801–induced memory impairments in a Y-maze spatial test, we observed a reversal upon the combination of BQCA with atypical antipsychotics, but not with haloperidol. These findings provide proof of concept that a judicious combination of existing antipsychotics with a selective M1 mAChR positive allosteric modulator can extend antipsychotic efficacy in glutamatergic deficit models of behavior.

Footnotes

    • Received June 7, 2016.
    • Accepted September 13, 2016.
  • ↵1 Current affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, United Kingdom.

  • This research was supported by the National Health and Medical Research Council (NHMRC) of Australia [Project Grant APP1052304 and Program Grant APP1055134]. A.C. and C.P. are NHMRC Senior Principal Research Fellows; P.M.S. is an NHMRC Principal Research Fellow; and J.R.L. is an NHMRC R.D. Wright Biomedical Career Development Fellow and Monash University Larkins Fellow.

  • dx.doi.org/10.1124/jpet.116.235788.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 359 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 359, Issue 2
1 Nov 2016
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Research ArticleDrug Discovery and Translational Medicine

M1 Positive Allosteric Modulation Improves Antipsychotic Efficacy

Kwok H. C. Choy, David M. Shackleford, Daniel T. Malone, Shailesh N. Mistry, Rahul T. Patil, Peter J. Scammells, Christopher J. Langmead, Christos Pantelis, Patrick M. Sexton, Johnathan R. Lane and Arthur Christopoulos
Journal of Pharmacology and Experimental Therapeutics November 1, 2016, 359 (2) 354-365; DOI: https://doi.org/10.1124/jpet.116.235788

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Research ArticleDrug Discovery and Translational Medicine

M1 Positive Allosteric Modulation Improves Antipsychotic Efficacy

Kwok H. C. Choy, David M. Shackleford, Daniel T. Malone, Shailesh N. Mistry, Rahul T. Patil, Peter J. Scammells, Christopher J. Langmead, Christos Pantelis, Patrick M. Sexton, Johnathan R. Lane and Arthur Christopoulos
Journal of Pharmacology and Experimental Therapeutics November 1, 2016, 359 (2) 354-365; DOI: https://doi.org/10.1124/jpet.116.235788
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