The behavioral profile of zolpidem, a novel hypnotic drug of imidazopyridine structure

The zolpidem discriminative cue is mediated by GABA A -␣ 1 receptors, whereas the chlordiazepoxide cue may be mediated via non-␣ 1 GABA A receptors because compounds with selective affinity for GABA A -␣ 1 receptors fully generalize to the former cue. We predicted that L-838,417 [7-tert-butyl-3-(2,5-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine], a partial agonist at non-␣ 1 GABA A receptors and an antagonist at GABA A -␣ 1 receptors, would generalize to the chlordiazepoxide but not the zolpidem-discriminative cue. SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one] is a full agonist at GABA A -␣ 2 receptors, with lower efficacy at GABA A -␣ 3 receptors and least efficacy at GABA A -␣ 1 and GABA A -␣ 5 receptors. Because SL651498 has efficacy at GABA A -␣ 1 receptors, we anticipated that it would generalize to both discriminative cues. Rats were trained to discriminate either zolpidem (3 mg/kg) or chlordiazepoxide (5 mg/kg) from vehicle using a two-lever operant procedure. The generalization profiles of L-838,417 and SL651498 were compared with nonselective full agonists, GABA A -␣ 1 -selective ligands zolpidem and CL218,872 [3-methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine], the nonselective partial agonist bretazenil, and the novel anxioselective drug ocinaplon. A nonselective partial agonist was included because L-838,417 and SL651498 are partial agonists at some GABA A receptors, and this property may influence their generalization profiles. All nonselective full agonists and ocinaplon fully generalized to both cues. CL218,872 and zolpidem generalized to zolpidem only, whereas L-838,417 fully generalized to chlordiazepoxide only. SL651498 fully generalized to chlordiazepoxide and occasioned significant zolpidem-appropriate responding. Bretazenil was similar to SL651498. In conclusion, at this training dose, the chlordiazepoxide-discriminative stimulus is mediated primarily via non-␣ 1 GABA A receptors and the generalization profiles of the ligands tested seem to correspond with their in vitro profiles at GABA A receptor subtypes.

Section: Discussioncontrasting

confidence: 94%

“…Full generalization to chlordiazepoxide by the nonselective full agonists lorazepam, midazolam, diazepam, triazolam, alprazolam, and zopiclone agrees with previous reports (Sanger et al, 1987;Sanger and Benavides, 1993). Likewise, we have shown that these compounds also all fully generalize to the zolpidem cue.…”

Section: Discussionsupporting

confidence: 92%

Comparative Cue Generalization Profiles of L-838, 417, SL651498, Zolpidem, CL218,872, Ocinaplon, Bretazenil, Zopiclone, and Various Benzodiazepines in Chlordiazepoxide and Zolpidem Drug Discrimination

Mirza

Rodgers²,

Mathiasen³

2005

“…Pharmacologically, various nonbenzodiazepine compounds have been described that show either selective affinity (e.g., zolpidem and indiplon) or selective efficacy (e.g., L-838,417, SL651498, TP003, TPA023) for subtypes of GABA A receptors (Sanger et al, 1987;McKernan et al, 2000;Griebel et al, 2001;Dias et al, 2005;Atack et al, 2006). Such selectivity profiles have been argued to be the basis for selective behavioral profiles of these compounds in rodents and in some cases man.…”

Section: Introductionmentioning

confidence: 99%

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

Mirza

Larsen²,

Mathiasen³

et al. 2008

The novel positive allosteric modulator NS11394 [3Ј-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] possesses a functional selectivity profile at GABA A receptors of ␣ 5 Ͼ ␣ 3 Ͼ ␣ 2 Ͼ ␣ 1 based on oocyte electrophysiology with human GABA A receptors. Compared with other subtype-selective ligands, NS11394 is unique in having superior efficacy at GABA A -␣ 3 receptors while maintaining low efficacy at GABA A -␣ 1 receptors. NS11394 has an excellent pharmacokinetic profile, which correlates with pharmacodynamic endpoints (CNS receptor occupancy), yielding a high level of confidence in deriving in vivo conclusions anchored to an in vitro selectivity profile and allowing for translation to higher species. Specifically, we show that NS11394 is potent and highly effective in rodent anxiety models. The anxiolytic efficacy of NS11394 is most probably mediated through its high efficacy at GABA A -␣ 3 receptors, although a contributory role of GABA A -␣ 2 receptors cannot be excluded. Compared with benzodiazepines, NS11394 has a significantly reduced side effect profile in rat (sedation, ataxia, and ethanol interaction) and mouse (sedation), even at full CNS receptor occupancy. We attribute this benign side effect profile to very low efficacy of NS11394 at GABA A -␣ 1 receptors and an overall partial agonist profile across receptor subtypes. However, NS11394 impairs memory in both rats and mice, which is possibly attributable to its efficacy at GABA A -␣ 5 receptors, albeit activity at this receptor might be relevant to its antinociceptive effects (J Pharmacol Exp Ther 327:doi;10.1124/jpet.108.144, 2008). In conclusion, NS11394 has a unique subtype-selective GABA A receptor profile and represents an excellent pharmacological tool to further our understanding on the relative contributions of GABA A receptor subtypes in various therapeutic areas.Preclinical studies using genetically modified mice suggest that GABA A -␣ 1 (Rudolph et al., 1999;McKernan et al., 2000), ␣ 2 (Low et al., 2000), and ␣ 5 (Collinson et al., 2002;Crestani et al., 2002)-containing receptors mediate the sedative/ motor-impairing, anxiolytic, and memory impairing effects of benzodiazepines, respectively. Pharmacologically, various nonbenzodiazepine compounds have been described that show either selective affinity (e.g., zolpidem and indiplon) or selective efficacy (e.g., L-838,417, SL651498, TP003, TPA023) for subtypes of GABA A receptors (Sanger et al., 1987;McKernan et al., 2000;Griebel et al., 2001;Dias et al., 2005;Atack et al., 2006). Such selectivity profiles have been argued to be the basis for selective behavioral profiles of these compounds in rodents and in some cases man. For example, zolpidem is selective for GABA A -␣ 1 -containing receptors, has a preferential sedative-hypnotic profile in animals, and is marketed as a sleep aid zolpidem tartrate (Ambien). Although additional compounds with various selectivity profiles have emerged, limited clinical data in patient populations exist to date (but see Basile...

“…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…”

mentioning

confidence: 99%

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

McMahon

Gerak

Carter³

et al. 2002

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 ...