The Anxioselective Agent 7-(2-Chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) Is More Efficacious Than Diazepam at Enhancing GABA-Gated Currents at α₁ Subunit-Containing GABA_A Receptors

Abstract

Studies using mice with point mutations of GABA A receptor ␣ subunits suggest that the sedative and anxiolytic properties of 1,4-benzodiazepines are mediated, respectively, by GABA A receptors bearing the ␣ 1 and ␣ 2 subunits. This hypothesis predicts that a compound with high efficacy at GABA A receptors containing the ␣ 1 subunit would produce sedation, whereas an agonist acting at ␣ 2 subunit-containing receptors (with low or null efficacy at ␣ 1 -containing receptors) would be anxioselective. Electrophysiological studies using recombinant GABA A receptors expressed in Xenopus oocytes indicate that maximal potentiation of GABA-stimulated currents by the pyrazolo-[1,5-a]-pyrimidine, DOV 51892, at ␣ 1 ␤ 2 ␥ 2S constructs of the GABA A receptor was significantly higher (148%) than diazepam. In contrast, DOV 51892 was considerably less efficacious and/or potent than diazepam in enhancing GABA-stimulated currents mediated by constructs containing ␣ 2 , ␣ 3 , or ␣ 5 subunits. In vivo, DOV 51892 increased punished responding in the Vogel conflict test, an effect blocked by flumazenil, and increased the percentage of time spent in the open arms of the elevated plus-maze. However, DOV 51892 had no consistent effects on motor function or muscle relaxation at doses more than 1 order of magnitude greater than the minimal effective anxiolytic dose. Although the mutant mouse data predict that the high-efficacy potentiation of GABA A1a receptor-mediated currents by DOV 51892 would be sedating, behavioral studies demonstrate that DOV 51892 is anxioselective, indicating that GABA potentiation mediated by ␣ 1 subunit-containing GABA A receptors may be neither the sole mechanism nor highly predictive of the sedative properties of benzodiazepine recognition site modulators.

Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects

“…Their in vivo profiles were mainly in line with the results of genetic studies, which, as a finding of special clinical relevance, associated motor impairing effects with activation of receptors containing the α 1 subunit (reviewed in Rudolph and Möhler, 2006). At the same time, there have been some promising developments also of ligands reportedly non-selective in affinity and efficacy at GABA A receptors (Auta et al, 2010; Rabe et al, 2007), or even predominantly active at receptors containing the α 1 subunit (Lippa et al, 2005; Popik et al, 2006), but still showing a low potential for motor deficits in animals. In order to shed some additional light on these apparently contradictory results, we discovered and pharmacologically characterized SH-I-048A, a non-selective ligand that exhibited an exceptional, subnanomolar capacity to bind to all four BZ-sensitive GABA A receptors and also strongly potentiated the inhibitory effect of GABA, mediated through these receptors.…”

“…Despite promising preclinical data, no clear clinical breakthroughs have been made to date (Atack et al 2011) and, indeed, the whole concept has been questioned to a certain degree (Skolnick, 2012). Especially puzzling were the results suggesting that substantial improvement in the behavioral profile may be accomplished by non-selective ligands active at all four populations of BZ-sensitive GABA A receptors (Auta et al, 2010; Rabe et al, 2007), or even predominantly active at GABA A receptors containing the α 1 subunit (Lippa et al, 2005; Popik et al, 2006). Such findings were clearly at odds with results from genetic studies showing that sedation and motor impairments exerted by BZs depend to a high degree on positive modulation of α 1 GABA A receptors (Atack, 2010).…”

Structure, Function, and Modulation of GABAA Receptors

“…Another example is pyrazolopyrimidine (DOV-51892), which is specific for ␣ 1 -containing receptors. Therefore, DOV-51892 is predicted to have sedative properties, but behavioral studies demonstrate that DOV-51892 is a non-sedative anxiolytic (90). At the moment, we should be careful to make any simplified statements.…”

Limiting Activity at β1-Subunit-Containing GABAA Receptor Subtypes Reduces Ataxia

“…A prominent example that argues against the theory is the BZ site ligand ocinaplon. It has robust full agonist-like activity at ␣ 1 -subunit-containing GABA A Rs in vitro, yet it has reduced sedative liability in preclinical and clinical studies (Basile et al, 2004;Lippa et al, 2005;Popik et al, 2006). Furthermore, there have been no reports of compounds with ␣ 2,3 -subunit selectivity achieving clinical proof-of-concept (i.e., anxioselectivity), despite the passage of almost a decade since the initial proposal of the ␣ 2,3 -subunit selectivity hypothesis.…”