The benzodiazepine binding site of GABA_A receptors as a target for the development of novel anxiolytics

Non-selective benzodiazepine (BZ) binding-site full agonists, exemplified by diazepam, act by enhancing the inhibitory effects of GABA at GABA_A receptors containing either an α₁, -₂, -₃ or -₅ subunit. However, despite their proven clinical anxiolytic efficacy, such compounds possess a relatively narrow window between doses that produce anxiolysis and those that cause sedation, and are also associated with physical dependence and a potential for abuse. In the late 1980s and early 1990s a number of non-selective partial agonists, exemplified by bretazenil, pazinaclone and abecarnil, were described. Their reduced intrinsic efficacy relative to full agonists such as diazepam resulted in an improved preclinical pharmacological profile in that there was a large window between anxiolytic and sedative doses and their dependence and abuse liabilities were much lower. Unfortunately, these compounds failed, for a variety of reasons, to translate into clinical benefit, and as the public perception of BZs deteriorated interest in the area waned. However, the advent of molecular genetic and pharmacological approaches has begun to delineate which GABA_A receptor subtypes are associated with the various pharmacological effects of the non-selective BZs. More specifically, the α₂- and/or α₃-containing GABA_A receptors play a role in anxiety whereas the α₁ subtype is involved in sedation, raising the possibility of a compound that selectively modulates α₂- and/or α₃-containing receptors but does not affect α₁-containing receptors would be a non-sedating anxiolytic. In order to achieve selectivity for the α₂/α₃ subtypes relative to α1, two approaches may be used; selective affinity or selective efficacy. Selective affinity relies on a compound binding with higher affinity to the α₂/α₃ compared with α₁ subtypes, but to date no such compounds have been described. On the other hand, subtype-selective efficacy relies on a compound binding to all subtypes but having different efficacies at various subtypes (relative selective efficacy, for example SL654198 or pagoclone) or having efficacy at some subtypes but none at others (absolute selective efficacy; for example, L-838417). The status of these and other BZ site compounds with claimed, but often not explicitly stated, GABA_A subtype selectivity (such as ELB-139 and ocinaplon) will be reviewed in relation to their development as non-sedating anxiolytics for the treatment of generalised anxiety disorder.