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
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doi:10.1124/jpet.103.063487.
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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.
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↵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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