Abstract

The novel positive allosteric modulator NS11394 [3′-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] possesses a functional selectivity profile at GABA_A receptors of α₅ > α₃ > α₂ > α₁ 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-α₃ receptors while maintaining low efficacy at GABA_A-α₁ 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-α₃ receptors, although a contributory role of GABA_A-α₂ 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-α₁ 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-α₅ 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.