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

Abstract

Indiplon (NBI 34060;-pyrazolo[1,5-␣]pyrimidin-7-yl]phenyl]acetamide), a novel pyrazolopyrimidine and high-affinity allosteric potentiator of GABA A receptor function, was profiled for its effects in rodents after oral administration. In mice, indiplon inhibited locomotor activity (ED 50 ϭ 2.7 mg/kg p.o.) at doses lower than the nonbenzodiazepine hypnotics zolpidem (ED 50 ϭ 6.1 mg/kg p.o.) and zaleplon (ED 50 ϭ 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 T max , short t 1/2 , 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 GABA A receptor function, with selectivity for ␣1 subunit-containing GABA A receptors.

Characterization of the Interaction of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic, with the GABAAReceptor

“…Indiplon acts in a subtype-selective manner consistent with selectivity for GABA A receptors containing the ␣1 subunit. These in vitro data are consistent with the in vivo pharmacology of indiplon (Foster et al, 2004), where indiplon acts as an effective sedative-hypnotic, which also possesses anxiolytic and anticonvulsant properties. These features, combined with a short half-life (t 1/2 ϭ 1 h after oral dosing in mouse and rat; Foster et al, 2004), have made indiplon an attractive candidate as an improved sedative-hypnotic agent to treat insomnia, a concept that is currently being evaluated in multiple clinical studies.…”

“…Both GABA shift experiments and patch-clamp recordings of rat cortical neurons in culture suggest that indiplon is a full agonist for the benzodiazepine site on native GABA A receptors. Overall, these data are consistent with the in vivo pharmacological profile of indiplon (Foster et al, 2004) as an effective sedative-hypnotic agent acting through the benzodiazepine site on the GABA A receptor.…”

“…1) with sedative and hypnotic properties mediated through potentiation of GABA A receptors (Foster et al, 2004). The present studies were conducted to define the interaction of indiplon with native GABA A receptors and to characterize the binding of [ …”

Effects of Menthol on the Pharmacokinetics of Triazolam and Phenytoin

“…25) Thus, the intake of menthol is expected to impair the QOL of patients who are being treated with triazolam.…”

Novos sedativos hipnóticos

“…2) Indiplona A indiplona é uma nova pirazolopirimidina com seletividade para receptores contendo a subunidade α1, e alguma seletividade para a subunidade α6 15 . Um estudo com polissonografia mostrou que indiplona promove redução da latência do sono, do número de despertares após o início do sono, além de não apresentar efeitos residuais diurnos devido a sua meia-vida curta 16 .…”