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

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Abstract
Non-selective benzodiazepine (BZ) binding-site full agonists, exemplified by diazepam, act by enhancing the inhibitory effects of GABA at GABAA 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...
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