Comparison of the pharmacological properties of classical and novel BZ-ω receptor ligands

Griebel, Guy; Perrault, Ghislaine; Tan, Sheng; Schoemaker, Hans E.; Dj, Sanger

doi:10.1097/00008877-199909000-00007

Cited by 40 publications

(15 citation statements)

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“…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). The basis for the effect of NS11394 on rat motility at doses suprathreshold for inducing full receptor occupancy are unclear but might feasibly be related to NS11394 acting at GABA A -␣ 4 -or ␣ 6 -containing receptors at high doses, because activation of these receptor subtypes induces motoric impairment (Ebert et al, 2006).…”

Section: Discussionmentioning

confidence: 96%

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

J Pharmacol Exp Ther

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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...

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Section: Discussionmentioning

confidence: 96%

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

J Pharmacol Exp Ther

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“…It could be argued that the preclinical profile of TPA023 is not dissimilar from that of nonselective partial agonists such as bretazenil, which in preclinical species is, like TPA023, also a nonsedating anxiolytic with a reduced ethanol interaction that shows little propensity to develop dependence and does not precipitate withdrawal from a full agonist (Haefely et al, 1990;Martin et al, 1995;Griebel et al, 1999). However, TPA023 differs in two important respects from nonselective full and partial BZ agonists such as diazepam and bretazenil: 1) it lacks efficacy at the ␣1 and ␣5 subtypes and therefore exerts its in vivo effects through ␣2-and ␣3-containing receptors rather than the ␣1, ␣2, ␣3, and ␣5 receptors modulated by the nonselective BZ agonists, and 2) it is a The GABA A ␣2/␣3 Agonist TPA023 Is a Nonsedating Anxiolytic 421 at ASPET Journals on May 9, 2018 jpet.aspetjournals.org weak partial agonist at the ␣2 and ␣3 subtypes, with an efficacy at the ␣2 and ␣3 subtypes of only 0.11 and 0.21% relative to chlordiazepoxide that is therefore considerably lower than that of bretazenil (Atack, 2003).…”

Section: Discussionmentioning

confidence: 99%

TPA023 [7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an Agonist Selective for α2- and α3-Containing GABA_AReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates

Atack

Wafford²,

Tye³

et al. 2005

J Pharmacol Exp Ther

173

182

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7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo [4,3-b]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABA A receptors containing an ␣1, ␣2, ␣3, or ␣5 subunit but has partial agonist efficacy at the ␣2 and ␣3 subtypes and essentially antagonist efficacy at the ␣1 and ␣5 subtypes. In rats, TPA023 gave time-and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1-3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N-methyl-␤-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel ␣2/␣3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.GABA A receptors are ligand-gated chloride ionophores that mediate the fast synaptic as well as tonic extrasynaptic inhibitory effects of GABA (Mody and Pearce, 2004). They are pentameric assemblies of proteins (Cromer et al., 2002) derived from a family of 16 genes (␣1-6, ␤1-3, ␥1-3, ␦, ⑀, , and ; Simon et al., 2004). Despite the theoretically large number of possible pentameric permutations that can arise from these 16 genes, only relatively few combinations are found within the central nervous system (McKernan and Whiting, 1996). Most of these native receptors contain ␣, ␤, and ␥ subunits in a 2:2:1 stoichiometry with an alternating ␣␤␣␤␥ arrangement as viewed from the synapse (Minier and Sigel, 2004).In addition to binding sites for their endogenous ligand, GABA A receptors also possess recognition sites for a number of pharmacologically active classes of compounds, including

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“…The VCT has played a key role in the characterisation of drugs acting on GABAergic, glutamatergic and monoaminergic neurotransmitter systems and, more recently, those acting at neuropeptide receptors (reviewed in Millan and Brocco 2003). Classical benzodiazepines reduce conflict behaviour in rats in the VCT, as measured by an increase in water intake in the presence of shock delivery (Millan and Brocco 2003;Loiseau et al 2003;Griebel et al 1999Griebel et al , 2002Sorbera et al 2001;Flores and Pellon 2000;Nazar et al 1997;Brocco et al 1990). Although similar effects of benzodiazepines have been shown in mice in the VCT, this species has not been routinely used (Liao et al 2003;Maruyama et al 2001;van Gaalen and Steckler 2000;Umezu 1995Umezu , 1999Kuribara et al 1989Kuribara et al , 1990.…”

Section: Introductionmentioning

confidence: 99%

A comparison of chlordiazepoxide, bretazenil, L838,417 and zolpidem in a validated mouse Vogel conflict test

Mathiasen

Mirza

2005

Psychopharmacology

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Comparison of the pharmacological properties of classical and novel BZ-ω receptor ligands

Cited by 40 publications

References 0 publications

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

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

TPA023 [7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an Agonist Selective for α2- and α3-Containing GABA_AReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates

A comparison of chlordiazepoxide, bretazenil, L838,417 and zolpidem in a validated mouse Vogel conflict test

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Comparison of the pharmacological properties of classical and novel BZ-ω receptor ligands

Cited by 40 publications

References 0 publications

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

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

TPA023 [7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an Agonist Selective for α2- and α3-Containing GABAAReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates

A comparison of chlordiazepoxide, bretazenil, L838,417 and zolpidem in a validated mouse Vogel conflict test

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Product

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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

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

TPA023 [7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an Agonist Selective for α2- and α3-Containing GABA_AReceptors, Is a Nonsedating Anxiolytic in Rodents and Primates