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Research ArticleNEUROPHARMACOLOGY

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

Alan C. Foster, Mary Ann Pelleymounter, Mary Jane Cullen, Dacie Lewis, Margaret Joppa, Ta Kung Chen, Haig P. Bozigian, Raymond S. Gross and Kathleen R. Gogas
Journal of Pharmacology and Experimental Therapeutics November 2004, 311 (2) 547-559; DOI: https://doi.org/10.1124/jpet.103.063487
Alan C. Foster
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Mary Ann Pelleymounter
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Mary Jane Cullen
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Dacie Lewis
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Margaret Joppa
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Ta Kung Chen
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Haig P. Bozigian
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Raymond S. Gross
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Kathleen R. Gogas
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Abstract

Indiplon (NBI 34060; N-methyl-N-[3-[3-(2-thienylcarbonyl)-pyrazolo[1,5-α]pyrimidin-7-yl]phenyl]acetamide), a novel pyrazolopyrimidine and high-affinity allosteric potentiator of GABAA receptor function, was profiled for its effects in rodents after oral administration. In mice, indiplon inhibited locomotor activity (ED50 = 2.7 mg/kg p.o.) at doses lower than the nonbenzodiazepine hypnotics zolpidem (ED50 = 6.1 mg/kg p.o.) and zaleplon (ED50 = 24.6 mg/kg p.o.), a sedative effect that was reversed by the benzodiazepine site antagonist flumazenil. Indiplon inhibited retention in the mouse passive avoidance paradigm over a dose range and with a temporal profile that coincided with its sedative activity. Indiplon, zolpidem, and zaleplon were equally effective in inhibiting locomotor activity in the rat and produced dose-related deficits on the rotarod. In a rat vigilance paradigm, indiplon, zolpidem, and zaleplon produced performance deficits over a dose range consistent with their sedative effects, although indiplon alone showed no significant increase in response latency. Indiplon produced a small deficit in the delayed nonmatch to sample paradigm at a dose where sedative effects became apparent. Indiplon was active in the rat Vogel test of anxiety, but it showed only a sedative profile in the mouse open field test. The pharmacokinetic profile of indiplon in both rat and mouse was consistent with its pharmacodynamic properties and indicated a rapid Tmax, short t1/2, and excellent blood-brain barrier penetration. Therefore, indiplon has the in vivo profile of an efficacious sedative-hypnotic, in agreement with its in vitro receptor pharmacology as a high-affinity allosteric potentiator of GABAA receptor function, with selectivity for α1 subunit-containing GABAA receptors.

Footnotes

  • doi:10.1124/jpet.103.063487.

  • ABBREVIATIONS: HBC, 2-hydroxypropyl-β-cyclodextran; ANOVA, analysis of variance; MED, minimal effective dose; HPMC, hydroxylpropylmethyl cellulose; Ro 15-1788, flumazenil; Ro 15-4513, ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]-[1,4]benzodiazepine-3-carboxylate.

  • ↵1 Current address: Department of Metabolic Research, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08543.

    • Received November 24, 2003.
    • Accepted February 20, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 311 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 2
1 Nov 2004
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Research ArticleNEUROPHARMACOLOGY

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

Alan C. Foster, Mary Ann Pelleymounter, Mary Jane Cullen, Dacie Lewis, Margaret Joppa, Ta Kung Chen, Haig P. Bozigian, Raymond S. Gross and Kathleen R. Gogas
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 547-559; DOI: https://doi.org/10.1124/jpet.103.063487

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Research ArticleNEUROPHARMACOLOGY

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

Alan C. Foster, Mary Ann Pelleymounter, Mary Jane Cullen, Dacie Lewis, Margaret Joppa, Ta Kung Chen, Haig P. Bozigian, Raymond S. Gross and Kathleen R. Gogas
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 547-559; DOI: https://doi.org/10.1124/jpet.103.063487
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