Abstract
The new generation hypnotic drugs, zolpidem, zopiclone and zaleplon, are at least as efficacious in the clinic as benzodiazepines and may offer advantages in terms of safety. These drugs act through the BZ binding sites associated with GABAA receptors, but show some differences from benzodiazepines in pharmacological effects and mechanisms of action. Of particular interest is the finding that zolpidem shows a wide separation between doses producing sedative effects and those giving rise to other behavioural actions, and induces less tolerance and dependence than benzodiazepines. Zolpidem also demonstrates selectivity for GABAA receptors containing α1 subunits. Recent studies using genetically modified mice have confirmed that receptors containing alpha1 subunits play a particularly important role in mediating sedative activity, thus providing an explanation for the pharmacological profile of zolpidem.
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References
Damgen K, Luddens H. Zaleplon displays a selectivity to recombinant GABAA receptors different from zolpidem, zopiclone and benzodiazepines. Neurosci Res Commun 1999; 25: 139–48
Perrault G, Morel E, Sanger DJ, et al. Differences in pharmacological profiles of a new generation of benzodiazepine and non-benzodiazepine hypnotics? Eur J Pharmacol 1990; 187: 487–94
Sanger DJ, Morel E, Perrault G. Comparison of the pharmacological profiles of the hypnotic drugs zaleplon and zolpidem. Eur J Pharmacol 1996; 313: 35–42
Dooley M, Plosker GL. Zaleplon. A review of its use in the treatment of insomnia. Drugs 2000; 50: 413–45
Sanger DJ, Benavides J, Perrault G, et al. Recent developments in the behavioral pharmacology of benzodiazepine (ω) receptors: evidence for the functional significance of receptor subtypes. Neurosci Biobehav Rev 1994; 18: 355–72
Sanger DJ, Zivkovic B. Investigation of the development of tolerance to the actions of zolpidem and midazolam. Neuropharmacol 1987; 26: 1513–8
Perrault G, Morel E, Sanger DJ, et al. Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem. J Pharmacol Exp Ther 1992; 263: 298–303
Schoch P, Moreau JL, Martin JR, et al. Aspects of benzodiazepine receptor structure and function with relevance to drug tolerance and dependence. Biochem Soc Symp 1993; 59: 121–34
Benavides J, Peny B, Durand A, et al. Comparative in vivo and in vitro regional selectivity of central w (benzodiazepine) site ligands inhibiting [3H]flumazenil binding in the rat central nervous system. J Pharmacol Exp Ther 1992; 263: 884–96
Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002; 300: 2–8
Pritchett DB, Seeburg PH. Gamma-aminobutyric acidA recepter α5-subunit creates novel type II benzodiazepine receptor pharmacology. J Neurochem 1990; 54: 1802–4
Rudolph U, Crestani F, Benke D, et al. Benzodiazepine actions mediated by specific γ-aminobutyric acid1 receptor subtypes. Nature 1999; 401: 796–806
Low K, Crestani F, Keist R, et al. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 2000; 290: 131–3
Crestani F, Martyin JR, Mohler H, et al. Mechanism of action of the hypnotic zolpidem in vivo. Br J Pharmacol 2000; 131: 1251–4
Doble A. New insights into the mechanism of action of hypnotics. J Psychopharmacol 1999; 13: S11–20
Graham D, Faure C, Besnard F, et al. Pharmacological profile of benzodiazepine site ligands with recombinant GABAA receptor subtypes. Eur Neuropsychopharm 1996; 6: 119–25
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Sanger, D.J. The Pharmacology and Mechanisms of Action of New Generation, Non-Benzodiazepine Hypnotic Agents. CNS Drugs 18 (Suppl 1), 9–15 (2004). https://doi.org/10.2165/00023210-200418001-00004
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DOI: https://doi.org/10.2165/00023210-200418001-00004