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Research ArticleBEHAVIORAL PHARMACOLOGY

Behavioral Characterization of the Novel GABAB Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

John F. Cryan, Peter H. Kelly, Frederique Chaperon, Conrad Gentsch, Cedric Mombereau, Kurt Lingenhoehl, Wolfgang Froestl, Bernhard Bettler, Klemens Kaupmann and Will P. J. M. Spooren
Journal of Pharmacology and Experimental Therapeutics September 2004, 310 (3) 952-963; DOI: https://doi.org/10.1124/jpet.104.066753
John F. Cryan
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Peter H. Kelly
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Frederique Chaperon
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Conrad Gentsch
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Cedric Mombereau
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Kurt Lingenhoehl
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Wolfgang Froestl
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Bernhard Bettler
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Klemens Kaupmann
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Will P. J. M. Spooren
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Abstract

The role of GABAB receptors in various behavioral processes has been largely defined using the prototypical GABAB receptor agonist baclofen. However, baclofen induces sedation, hypothermia and muscle relaxation, which may interfere with its use in behavioral paradigms. Although there is much evidence for a role of the inhibitory neurotransmitter GABA in the pathophysiology of anxiety, the role of GABAB receptors in these disorders is largely unclear. We recently identified GS39783 (N,N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) as a selective allosteric positive modulator at GABAB receptors. The aim of the present study was to broadly characterize the effects of GS39783 in well-validated rodent models for motor activity, cognition, and anxiety. The following tests were included: locomotor activity in rats and mice, rotarod and traction tests (including determinations of core temperature) in mice, passive avoidance in mice and rats, elevated plus maze in rats, elevated zero maze in mice and rats, stress-induced hyperthermia in mice, and pentobarbital- and ethanol-induced sleep in mice. Unlike baclofen and/or the benzodiazepine chlordiazepoxide, GS39783 had no effect in any of the tests for locomotion, cognition, temperature, or narcosis. Most interestingly, GS39783 had anxiolytic-like effects in all the tests used. Overall, the data obtained here suggest that positive modulation of GABAB receptors may serve as a novel therapeutic strategy for the development of anxiolytics, with a superior side effect profile to both baclofen and benzodiazepines.

Footnotes

  • This work was supported by National Institutes of Mental Health/National Institute on Drug Abuse Grant U01 MH69062 (to J.F.C., W.F., and K.K.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.104.066753.

  • ABBREVIATIONS: [35S]GTPγS, guanosine 5′-O-(thio)triphosphate; GS39783, N,N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; CDZ, chlordiazepoxide; ANOVA, analysis of variance; CGP55845A, [3-[[1-(S)-(3,4-dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]phenylmethyl-phosphinic acid hydrochloride; SIH, stress-induced hyperthermia.

  • ↵1 C.M. is a doctoral student affiliated with the Laboratoire de Neuroscience Cognitives, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5106, Université de Bordeaux 1, Avenue des Facultés, Talence cedex 33405, France.

  • ↵2 Present address: Pharmazentrum, Department of Clinical-Biological Sciences, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.

  • ↵3 Present address: F-Hoffmann La Roche, Basel, Switzerland.

    • Received February 11, 2004.
    • Accepted April 26, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 3
1 Sep 2004
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Behavioral Characterization of the Novel GABAB Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines
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Research ArticleBEHAVIORAL PHARMACOLOGY

Behavioral Characterization of the Novel GABAB Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

John F. Cryan, Peter H. Kelly, Frederique Chaperon, Conrad Gentsch, Cedric Mombereau, Kurt Lingenhoehl, Wolfgang Froestl, Bernhard Bettler, Klemens Kaupmann and Will P. J. M. Spooren
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 952-963; DOI: https://doi.org/10.1124/jpet.104.066753

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Research ArticleBEHAVIORAL PHARMACOLOGY

Behavioral Characterization of the Novel GABAB Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

John F. Cryan, Peter H. Kelly, Frederique Chaperon, Conrad Gentsch, Cedric Mombereau, Kurt Lingenhoehl, Wolfgang Froestl, Bernhard Bettler, Klemens Kaupmann and Will P. J. M. Spooren
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 952-963; DOI: https://doi.org/10.1124/jpet.104.066753
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