Differences in pharmacological profiles of a new generation of benzodiazepine and non-benzodiazepine hypnotics

Perrault, Ghislaine; Morel, E; Sanger, D. J.; Živković, B.

doi:10.1016/0014-2999(90)90375-g

Cited by 85 publications

(32 citation statements)

References 30 publications

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“…These findings suggest that 1.5 mg/kg might be the minimal effective dose to produce an antiaggressive action, at least when an animal model of isolation-induced aggression is used. In addition, the failure of zopiclone to produce motor impairment agrees with several studies in which are required higher doses of zopiclone to reduce spontaneous locomotor activity (11.5 mg/kg, intraperitoneally) [Perrault et al, 1990] and to produce ataxia in the rotarod test (25 mg/kg, intraperitoneally) in mice . On the other hand, our results are similar to those described with benzodiazepines.…”

Section: Discussionsupporting

confidence: 69%

Antiaggressive Effects of Zolpidem and Zopiclone in Agonistic Encounters Between Male Mice

Martı́n-López

Navarro

2002

Aggressive Behavior

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The effects of benzodiazepines on various types of aggression have been extensively studied. These substances produce their pharmacological effects by allosterically modulating the action of GABA via specific recognition sites on the GABA A receptor called omega 1 and omega 2. The antiaggressive profile of non-benzodiazepine compounds that also act at omega sites, such as zopiclone (a non-selective omega 1 and 2 ligand) and zolpidem (a selective omega 1 ligand) has been scarcely explored. In this study, we examined the action of zolpidem (0.75-3 mg/kg, intraperitoneally) and zopiclone (1.5-6 mg/ kg), administered acutely or subchronically for 10 days, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic ''standard opponents'' 30 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. Acute treatment with zopiclone produced a marked antiaggressive effect, reducing offensive behaviors (threat and attack) at all doses used (1.5, 3, and 6 mg/kg) without affecting immobility. Likewise, the intermediate dose of zolpidem (1.5 mg/kg) significantly decreased aggression in a specific manner, without altering immobility, whereas the highest dose (3 mg/kg) provoked a reduction of aggression accompanied by a weak (but significant) increase of immobility. With repeated treatment, no tolerance to the antiaggressive effects of zopiclone and zolpidem was developed. It is concluded that omega sites at the GABA A receptor could be involved in the control of aggression. Aggr. Behav. 28:416-425, 2002. r

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Section: Discussionsupporting

confidence: 69%

Antiaggressive Effects of Zolpidem and Zopiclone in Agonistic Encounters Between Male Mice

Martı́n-López

Navarro

2002

Aggressive Behavior

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“…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). Zaleplon has a half-life of 1 h in humans after oral administration (Greenblatt et al, 1998); however, this compound has a lower affinity than zolpidem at benzodiazepine binding sites and a reduced selectivity for ␣1 subunit-containing GABA A receptors (Damgen and Luddens, 1999).…”

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confidence: 99%

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

Foster¹,

Pelleymounter²,

Cullen³

et al. 2004

J Pharmacol Exp Ther

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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.

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“…This might be explained by the selective on affinity of zolpidem, compared with the as elective receptor binding of the benzodiazepines (wI and (02). 7,25,26 A tapering off and washout period should, therefore, be considered before switching from benzodiazepines to zolpidem. The patient should be well informed and motivated for this switch, because of the possible withdrawal period, after long-term benzodiazepine use.…”

Section: Discussionmentioning

confidence: 99%

“…The benzodiazepines act on all subtypes (001, 002) of the benzodiazepine receptor, which could explain their anxiolytic, myorelaxant and anticonvulsant properties. 7 The pharmacological profile of zolpidem differs from that of the benzodiazepines: it is a short-acting imidazopyridine, showing a selective affinity for the ort-subtype receptor while it is almost devoid of affinity for m2-subtype receptor." As a result of this selective ml-receptor binding, zolpidem is likely to cause a lower overall receptor occupancy compared with the benzcdiazepines."…”

Section: Introductionmentioning

confidence: 99%

“…This may explain zolpidem's clinical profile, which at a therapeutic dose shows a marked sedative effect, while it has virtually no anxiolytic, myorelaxant or anticonvulsant effects. 7 Zolpidem has a rapid onset of action and does not negatively affect physiological 254 sleep architecture.!? - 12 It has been observed that cessation of zolpidem treatment does not induce significant rebound insomnia or withdrawal manifestations.w-> It is not known whether treatment of insomnia with a non-benzodiazepine such as zolpidem induces a more natural sleep in patients with chronic insomnia, after the cessation of long-term use of benzodiazepines.…”

Section: Introductionmentioning

confidence: 99%

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Zolpidem, a Valuable Alternative to Benzodiazepine Hypnotics for Chronic Insomnia?

Declerck

Smits

1999

J Int Med Res

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Sleep quality and anxiety levels were examined using questionnaires and polysomnographic recordings in 22 chronic insomnia patients who regularly used benzodiazepines to treat their sleeping problems. After abruptly discontinuing their benzodiazepine medication, patients were randomly allocated to receive either a placebo or zolpidem 10 mg for 1 week, after which they entered an open extension phase, receiving zolpidem 10 mg for 3 weeks. Subjectively, sleep quality was considered mediocre during the use of a benzodiazepine hypnotic. One week after the discontinuation, an increase in sleep latency was observed in the placebo group, whereas zolpidem induced a significant decrease in sleep latency. Deterioration of other sleep variables (probably rebound) was not suppressed by zolpidem. An explanation for this could be the selective pharmacological profile of zolpidem. Polysomnographic differences between placebo and benzodiazepine and between placebo and zolpidem were not reflected by the subjective data on sleep and anxiety. Changes of sleep structure caused by hypnotics seem not always to be felt as such by patients. After 3 – 4 weeks of zolpidem treatment, the percentage of non-rapid eye movement-4 sleep increased significantly, corresponding with a significant subjective improvement of sleep quality. This indicates that zolpidem may restore physiological sleep.

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Differences in pharmacological profiles of a new generation of benzodiazepine and non-benzodiazepine hypnotics

Cited by 85 publications

References 30 publications

Antiaggressive Effects of Zolpidem and Zopiclone in Agonistic Encounters Between Male Mice

Antiaggressive Effects of Zolpidem and Zopiclone in Agonistic Encounters Between Male Mice

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

Zolpidem, a Valuable Alternative to Benzodiazepine Hypnotics for Chronic Insomnia?

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