Pharmacological profile of the imidazopyridine zolpidem at benzodiazepine receptors and electrocorticogram in rats

Abstract

Zolpidem is a novel non-benzodiazepine related hypnotic, which possesses an imidazopyridine structure. This drug has preferential affinity for the 3H-diazepam binding site in the rat cerebellum, while it is only weakly active at inhibiting 3H-Ro 5-4864 binding to the rat kidney. The potency of zolpidem at displacing 3H-Ro 15-1788 binding to rat cerebral cortex membranes is enhanced in the presence of GABA. On the sleep pattern of the electrocorticogram in the curarised rat, zolpidem induces a physiological type of slow wave sleep with rapid onset of action. Zolpidem differs from classical benzodiazepine drugs, in possessing an atypical binding profile to 3H-benzodiazepine receptors, and because it does not affect the sleep patterns.

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

“…The advantages of these newer agents over benzodiazepines seem to result from their mode of interaction with the GABA A receptor combined with a reduced duration of action. Thus, for example, zolpidem has a moderate affinity for ␣1-containing GABA A receptors in radioligand binding experiments (10 -100 nM; Arbilla et al, 1985;Smith et al, 2001;Sullivan et al, 2004), is fully efficacious (Smith et al, 2001;Sullivan et al, 2004), has selectivity for GABA A receptors containing the ␣1 subunit (Damgen and Luddens, 1999;Smith et al, 2001), produces sedative activity in animals that is mediated through ␣1 subunit-containing GABA A receptors , and has a half-life in rodents and humans after oral administration of 2 to 3 h (Gaudreault et al, 1995;Greenblatt et al, 1998). Zopiclone displays a similar efficacy profile in animal tests (Perrault et al, 1990), but it has only marginal selectivity for GABA A receptors containing the ␣1 subunit (Damgen and Luddens, 1999;Smith et al, 2001) and its half-life in humans of 3.5 to 6.5 h (Fernandez et al, 1995) has been associated with next day hangover effects, including impaired driving ability (Bocca et al, 1999;Vermeeren et al, 2002).…”

Mechanism of action of the hypnotic zolpidem in vivo

“…However, this view was in con¯ict with the characterization of the similarly a 1 -selective imidazopyridine alpidem as a selective anxiolytic (Zivkovic et al, 1990;Morselli, 1993). The extraordinary strong GABA shift for zolpidem ± an increase in the anity of zolpidem by a factor of 3 in the presence of 100 mM GABA in vitro ± was considered as alternative explanation for the preferential sedative-hypnotic eect of zolpidem (Arbilla et al, 1985;Depoortere et al, 1986). Thus, it has remained unclear whether the sedative-hypnotic eect of zolpidem in vivo is exclusively due to its interaction with a 1 -GABA A receptors, or due to a combined interaction with a 1 -, a 2 -and a 3 -GABA A receptors or whether it is mainly determined by its failure to modulate the neuronal populations expressing a 5 -GABA A receptors.…”

“…In contrast, the imidazopyridine hypnotic zolpidem is a ligand with a preferential anity for a 1 -GABA A receptor subtype as determined by radioligand binding studies in vitro (Arbilla et al, 1985;Depoortere et al, 1986;Bartholini, 1993). However, it had not been clari®ed whether its interactions with a 1 -GABA A receptors is indeed the basis for its sedativehypnotic activity.…”

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

“…Zolpidem has a very high affinity for receptors containing the α1 subunit, has an intermediate affinity for receptors that contain α2 or α3, and does not interact with GABA A receptors consisting of the α5 subunit [3][4][5][6] . In addition to its sedative effects, zolpidem has considerable anticonvulsant activity [7,8] .…”