Development of subtype-selective GABAA receptor compounds for the treatment of anxiety, sleep disorders and epilepsy

There is little doubt regarding the therapeutic possibilities of modulation of GABAA receptor function as exemplified by the clinical utility of benzodiazepines for half a century. The emerging understanding of the role of different GABAA receptor subtypes in mediating different physiological functions and pathological processes continues to offer opportunities for novel therapeutics. However, the challenge remains in turning the increased understanding of molecular pharmacology of GABAA receptors into clinically efficacious drugs. Probably the most active area of research has been the search for a non-sedating anxiolytic that acts via the benzodiazepine binding site. Unfortunately, the clinical development of a number of drugs with promising pre-clinical profiles, such as ocinaplon, SL65.1498, pagoclone, MRK-409, TPA023 and TPA023B has halted for a variety of reasons. Therefore, the underlying hypothesis that sub-type-selective compounds are non-sedating anxiolytics in man remains to be adequately tested. As regards hypnotics, the benzodiazepine site compounds adipiplon and indiplon, as well as the GABAA α4βδ-preferring agonist gaboxadol, are no longer in clinical development, leaving EVT-201, which has demonstrated efficacy in Phase II studies in primary insomnia, as the single, novel GABAA-mediated hypnotic currently under evaluation. Benzodiazepines remain the first-line treatment for status epilepticus, an indication for which, therefore, there would appear little need for GABAA subtype-selective compounds. With respect to epilepsy, modulation of GABAA receptor function via the neurosteroid recognition site is the mechanism of action of ganaxolone, which is currently being evaluated in Phase III studies in adult partial seizures and children with infantile seizures. The continually evolving understanding of the structure and function of not only the GABAA receptor but also the variety of diverse binding sites that it harbours should continue to provide the molecular basis for designing strategies to selectively modulate the function of distinct subtypes of the GABAA receptor and thereby provide novel therapies for the treatment of anxiety, sleep disorders, and possibly also epilepsy