Do Subtype-Selective γ-Aminobutyric Acid_A Receptor Modulators Have a Reduced Propensity to Induce Physical Dependence in Mice?

Abstract

Recent evidence suggests that GABA A receptors containing an ␣ 1 subunit mediate the sedative effect of diazepam, whereas receptors with an ␣ 2 subunit mediate this benzodiazepine's anxiolytic effect. Thus, compounds selective for GABA A -␣ 2 receptors may offer advantages, i.e., lack of sedation, over current benzodiazepines. Whether such compounds would offer additional advantages over benzodiazepines is unclear. Here, we address the issue of physical dependence by comparing the GABA A -␣ 1 affinity-selective drug zolpidem, the novel com- In the precipitated withdrawal model, compounds were administered at a dose giving ϳ80% receptor occupancy, obviating major differences in central nervous system bioavailability. Mice were administered compounds twice daily for 4 days and on day 5, 20 h after the final dose, given a dose of FG-7142 (40 mg/kg i.p.) that did not induce seizures in control animals. In mice treated with the three subtype-selective compounds, FG-7142 did not induce seizures. Moreover, there was a low propensity for FG-7142 to induce seizures in animals treated with the partial agonists, whereas seizures were clearly seen in animals treated with most benzodiazepines. Nonetheless, differences among the benzodiazepines themselves, similarities between the partial agonists and subtype-selective compounds, the in vitro/in vivo potency, and in vivo receptor exposure time data suggest a complex interaction among selectivity, efficacy, potency, and receptor exposure in determining physical dependence liability of benzodiazepine site modulators in mice.

NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a Unique Subtype-Selective GABAA Receptor Positive Allosteric Modulator: In Vitro Actions, Pharmacokinetic Properties and in Vivo Anxiolytic Efficacy

“…Thus, NS11394 has a benign side effect profile, even at doses suprathreshold for inducing full receptor occupancy in forebrain. By contrast, diazepam significantly reduced locomotor activity in mouse and rat, impaired rat rotarod performance, and engendered considerable ethanol interaction at doses (0.3-3 mg/kg) that could readily be ascribed to occupancy at GABA A receptors (Mirza and Nielsen, 2006). The doses of diazepam engendering side effects clearly overlap with doses effective in animal models of anxiety (e.g., Griebel et al, 1999a;Mathiasen et al, 2007).…”

“…In this, the first of two articles, we introduce NS11394 as a novel subtype-selective GABA A receptor positive allosteric modulator and highlight: i) its in vitro binding and electrophysiology profile at human GABA A receptors, as well as its selectivity over other targets; ii) its excellent pharmacokinetic profile in rodents; iii) the close correlation observed between pharmacokinetic and pharmacodynamic (receptor occupancy) properties; iv) its in vivo profile in animal models of anxiety-like behavior, in addition to its in vivo side effect profile in comparison to various benzodiazepine site-positive modulators. We chose to compare NS11394 to alprazolam, diazepam, or chlordiazepoxide in the efficacy and side effect models, because it is clear that benzodiazepines differ considerably on various parameters, including potency, half-life, selectivity, and metabolite formation to name a few (Chouinard, 2004;Mirza and Nielsen, 2006). Given these differences, we were keen not to restrict ourselves to comparing NS11394 to a single representative for the entire benzodiazepine class, albeit at the expense of not being exhaustive in profiling all three benzodiazepines in all models.…”

Comparison of the Novel Subtype-Selective GABAA Receptor-Positive Allosteric Modulator NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] with Diazepam, Zolpidem, Bretazenil, and Gaboxadol in Rat Models of Inflammatory and Neuropathic Pain

“…3 H]flunitrazepam binding to rat cortex [Ͼ90% for diazepam (10 mg/kg), bretazenil (5 mg/kg), and NS11394 (5 mg/kg) and ϳ70% for zolpidem (20 mg/kg)] (unpublished data; see also Mirza and Nielsen, 2006;Mirza et al, 2008). Although zolpidem appeared at the bottom end of the desired range, this is slightly misleading due to its affinity selectivity for GABA A -␣ 1 receptors (Sanger and Benavides, 1993).…”

Use of a Novel Mouse Genotype to Model Acute Benzodiazepine Withdrawal

“…3 in Crabbe (1992) for the results of testing 1 and 2 mg/kg in WSP mice b All mice were injected with a benzodiazepine antagonist, flumazenil (10 mg/kg), at either 20 or 60 min after BZR agonist or vehicle injection -: Not determined; None: none seen: drug group's score was less than vehicle group's score McKernan et al 2000). For example, zolpidem is more selective for benzodiazepine receptors formed with a 1 subunits of the GABA A receptor complex, while classical benzodiazepines, like diazepam or lorazepam, bind to several a subunit subtypes (Mirza and Nielsen 2006). NMRI mice were administered diazepam, alprazolam, clonazepam, lorazepam, midazolam, triazolam, or zolpidem along with several other drugs (Mirza and Nielsen 2006).…”

“…Scores of 4-5 are given for Imidazo-benzodiazepine 1-2 No a Based on effect of ligand binding on magnitude of GABA agonist-stimulated chloride influx. Agonists enhance, inverse agonists reduce, and antagonists prevent agonists and inverse agonists from modulating chloride flux (Sieghart 1992) b Karara et al (1996), Tefakis Karavokiros and Tsipis (1990), Mirza and Nielsen (2006); estimated in humans. Compounds with active metabolites have functionally longer half-lives than the parent compounds the same seizure signs after only a lift, while scores of 3 and 6 are given for tonic-clonic convulsions upon spinning and lifting only, respectively.…”