Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem

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

doi:10.1016/0014-2999(96)00510-9

Cited by 97 publications

(50 citation statements)

References 29 publications

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“…Nevertheless, the latter explanation is not highly probable for the tested ligands with very low efficacies at a1-containing subtypes. Namely, even the preferential a1 subunit-selective agonist, zolpidem, does not possess more than 4.3 and 2.5 times greater potency to decrease locomotor activity compared to rotarod impairment in rats and mice, respectively (Sanger et al, 1996), whereas nonsubtype-selective agonists, such as diazepam, may be even more potent in exerting rotarod impairment than locomotor hypoactivity (Savić et al, 2003).…”

Section: Discussionmentioning

confidence: 95%

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Savić

Huang

Furtmüller

et al. 2007

Neuropsychopharmacol

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Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA A receptors containing a 1 , a 2 , a 3 or a 5 subunits. Genetic studies suggest that modulation at the a 1 subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA A receptors containing the a 1 subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA A receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for a 2 -, a 3 -, and a 5 -containing subtypes of GABA A receptors (SH-053-S-CH3 and SH-053-S-CH3-2 0 F) or essentially selective for a 5 subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of a 1 subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2 0 F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by a 5 -containing GABA A receptors. Hence, it could be of importance to avoid substantial agonist activity at a 5 receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.

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Section: Discussionmentioning

confidence: 95%

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Savić

Huang

Furtmüller

et al. 2007

Neuropsychopharmacol

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“…Ganaxolone, however, does induce crosstolerance to the anticonvulsant effect of diazepam (Reddy and Rogawski, 2000), an effect that cannot be explained by our present results but may possibly be due to posttranslational modification of receptor subunits. Chronic treatment of mice with zaleplon, zolpidem, or imidazenil, none of which modifies GABA A receptor subunit gene expression after longterm treatment in cultured cerebellar granule cells (Follesa et al, 2002), also does not induce tolerance (Ghiani et al, 1994;Sanger et al, 1996). It is quite surprising the finding that ganaxolone does not alter the GABA A receptor gene expression upon long-term exposure of cultured cerebellar granule cells in spite of being very similar, for chemical and …”

Section: Discussionmentioning

confidence: 99%

Changes in GABA_A Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells

Mascia

Biggio

Mancuso

et al. 2002

J Pharmacol Exp Ther

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The effects of ganaxolone, a synthetic analog of the endogenous neuroactive steroid allopregnanolone, on the function and expression of GABA A receptors were determined. Electrophysiological recordings demonstrated that ganaxolone potentiated with a potency and efficacy similar to those of allopregnanolone the Cl Ϫ currents evoked by GABA at recombinant human GABA A receptors (comprising ␣1␤2␥2L or ␣2␤2␥2L subunit assemblies) expressed in Xenopus oocytes. Exposure of cultured rat cerebellar granule cells to 1 M ganaxolone for 5 days had no effect on the abundance of mRNAs encoding the ␣1, ␣2, ␣3, ␣4, ␣5, ␥2L, or ␥2S subunits of the GABA A receptor. Withdrawal of ganaxolone after such long-term treatment, however, induced an increase in the abundance of ␣2, ␣4, and ␣5 subunit mRNAs and a decrease in the amounts of ␣1, ␥2L, and ␥2S subunit mRNAs. These changes were maximal 3 to 6 h after drug withdrawal and were reversible, being no longer apparent after 24 h. These results suggest that long-term exposure of cerebellar granule cells to ganaxolone does not affect the sensitivity of the GABA A receptor to several positive modulators. Nevertheless, the reduction in the amounts of the ␣1 and ␥2 subunit mRNAs together with the increase in the abundance of the ␣4 subunit mRNA induced by abrupt discontinuation of long-term treatment with ganaxolone suggest that withdrawal of this drug might result in a reduced response to classic benzodiazepines.GABA A receptor is the main type of inhibitory receptor in the brain and is a member of the superfamily of ligand-gated ion channels that includes the strychnine-sensitive glycine receptor, the 5-hydroxytryptamine 3 subtype of the serotonin receptor, and the nicotinic acetylcholine receptor (Betz, 1990). The binding of GABA to GABA A receptors induces the opening of an intrinsic Cl Ϫ channel with consequent hyperpolarization of the cell. The subunit composition of the pentameric GABA A receptors determines their specific physiological and pharmacological properties (Rudolph et al., 2001). The GABA A receptor is a prominent target of certain neuroactive steroids, which act as potent endogenous allosteric (positive or negative) modulators of receptor activity (ParkChung et al., 1999). Such compounds are also thought to be of potential therapeutic benefit. Indeed, neuroactive steroids have been used as intravenous anesthetics and have been shown to exert anxiolytic, hypnotic, anticonvulsant, and antiepileptic effects in animals or humans (Gasior et al., 1999).Ganaxolone (3␣-hydroxy-3␤-methyl-5␣-pregnan-20-one) is a synthetic compound that is structurally related to the endogenous neurosteroid allopregnanolone (3␣-hydroxy-5␣-pregnan-20-one) (Gasior et al., 1999). Like its endogenous analog, ganaxolone is a potent anticonvulsive and antiepileptic agent; however, it is more stable than allopregnanolone as a result of its ␤-methyl group, which prevents its metabolism and oxidation of the 3␣-hydroxy moiety (Carter et al., 1997 (Carter et al., 1997). In addition, ganaxolone is mor...

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“…For example, zaleplon and zolpidem do not consistently cross-substitute with nonselective BZs and other positive GABA A modulators (Depoortere et al, 1986;Sanger and Zivkovic, 1986;Vanover and Barrett, 1994;Sannerud and Ator, 1995;Ator and Kautz, 2000 for exception). Moreover, zaleplon and zolpidem are more potent in behavioral assays predictive of sedative activity as compared with other types of assays (Depoortere et al, 1986;Sanger and Zivkovic, 1988;Sanger et al, 1996). The apparently unique behavioral profile of zaleplon and zolpidem in rodents has been attributed to the selectivity of these drugs for BZ 1 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Selectivity at BZ 1 receptors might be responsible for zaleplon and zolpidem having behavioral effects that differ from those of nonselective BZs. For example, in rodents, zaleplon and zolpidem preferentially elicit sedative-hypnotic effects and do not share discriminative stimulus effects with other positive GABA A modulators (Depoortere et al, 1986;Sanger and Zivkovic, 1986;Sanger et al, 1987Sanger et al, , 1996Vanover and Barrett, 1994; Ator and Kautz, 2000 for exception). However, in primate species, zaleplon and zolpidem share discriminative stimulus and subject-rated effects with other positive GABA A modulators (Griffiths et al…”

Section: Introductionmentioning

confidence: 99%

Discriminative Stimulus Effects of Benzodiazepine (BZ)₁ Receptor-Selective Ligands in Rhesus Monkeys

McMahon

Gerak

Carter³

et al. 2002

J Pharmacol Exp Ther

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Drug discrimination was used to examine the effects of benzodiazepine (BZ) 1 receptor-selective ligands in rhesus monkeys. In diazepam-treated (5.6 mg/kg, p.o.) monkeys discriminating the nonselective BZ antagonist flumazenil (0.32 mg/kg, s.c.), the BZ 1 -selective antagonist ␤-carboline-3-carboxylate-t-butyl ester (␤-CCt) substituted for flumazenil. The onset of action of ␤-CCt was delayed with a dose of 5.6 mg/kg ␤-CCt substituting for flumazenil 2 h after injection. In monkeys discriminating the nonselective BZ agonist midazolam (0.56 mg/kg, s.c.), the BZ 1 -selective agonists zaleplon (ED 50 ϭ 0.78 mg/kg) and zolpidem (ED 50 ϭ 1.73 mg/kg) substituted for midazolam. The discriminative stimulus effects of midazolam, zaleplon, and zolpidem were antagonized by ␤-CCt (1.0 -5.6 mg/kg, s.c.), and the effects of zaleplon and zolpidem were also antagonized by flumazenil (0.01-0.32 mg/kg, s.c.). Schild analyses supported the notion of a simple, competitive interaction between ␤-CCt and midazolam (slope ϭ Ϫ1.08; apparent pA 2 ϭ 5.41) or zaleplon (slope ϭ Ϫ1.57; apparent pA 2 ϭ 5.49) and not between ␤-CCt and zolpidem. Schild analyses also were consistent with a simple, competitive interaction between flumazenil and zaleplon (slope ϭ Ϫ1.03; apparent pA 2 ϭ 7.45) or zolpidem (slope ϭ Ϫ1.11; apparent pA 2 ϭ 7.63). These results suggest that the same BZ receptor subtype(s) mediate(s) the effects of midazolam, zolpidem, and zaleplon under these conditions and that selective binding of BZ ligands does not necessarily confer selective effects in vivo.Drugs facilitating GABA A -mediated chloride flux (e.g., agonists; positive GABA A modulators) at benzodiazepine (BZ) receptors elicit sedative-hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects with an improved margin of safety compared with other positive GABA A modulators (e.g., barbiturates; for review, see Woods et al., 1992). Different BZ receptors comprise at least one of six different protein subunits designated ␣ 1-6 and are divided into two subtypes: BZ 1 receptors containing ␣ 1 -subunits and BZ 2 receptors containing ␣ 2 -, ␣ 3 -, or ␣ 5 -subunits (Sanger et al., 1994 for review). A more recent nomenclature adopted by the International Union of Pharmacology proposes an alternative designation for BZ receptors (Barnard et al., 1998). It has been postulated that the various effects elicited by BZ site ligands are mediated by different BZ receptor subtypes. This notion has been supported by transgenic mouse studies showing that mutations targeted at ␣ 2 subunits decrease the anxiolytic effects of BZs, whereas mutations targeted at ␣ 1 subunits decrease the sedative-hypnotic effects of BZs (Rudolph et al., 1999;McKernan et al., 2000).Most BZ receptor ligands have relatively little selectivity for particular BZ receptor subtypes, making it difficult to differentiate the functional significance of BZ receptor heterogeneity. BZs such as diazepam and midazolam are nonselective (Huang et al., 2000), whereas non-BZ compounds such as zaleplon and zolpidem ...

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Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem

Cited by 97 publications

References 29 publications

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Changes in GABA_A Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells

Discriminative Stimulus Effects of Benzodiazepine (BZ)₁ Receptor-Selective Ligands in Rhesus Monkeys

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Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem

Cited by 97 publications

References 29 publications

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Changes in GABAA Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells

Discriminative Stimulus Effects of Benzodiazepine (BZ)1 Receptor-Selective Ligands in Rhesus Monkeys

Contact Info

Product

Resources

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Changes in GABA_A Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells

Discriminative Stimulus Effects of Benzodiazepine (BZ)₁ Receptor-Selective Ligands in Rhesus Monkeys