Benzodiazepine recognition site ligands and GABA_A receptors

Abstract

The benzodiazepine recognition site of the mammalian brain GABA_A receptor (responsible for the majority of neuronal inhibition in the mammalian CNS) has taken its name from the chemical structures that we now know to interact specifically with this allosteric site. These benzodiazepines were introduced into clinical practice in the 1960s and proved to be enormously successful in the treatment of anxiety and sleep disorders. The pharmacological spectrum of activity for benzodiazepine site ligands is much wider. While it was recognised early that benzodiazepines were efficacious anticonvulsants and muscle relaxants, advances in our understanding of their mechanisms of action over the intervening years have revealed even greater potential for their clinical use. Early attempts to decrease the sedative potential of the benzodiazepine ligands, without losing their anxiolytic activity, proved frustratingly difficult. Meanwhile, the exciting potential of partial inverse agonists at this site to improve performance in certain cognitive tasks appeared to be confounded by their proconvulsant activity. This review briefly summarises some of the progress that has been made, and attempts to put the potential for further exploitation of this allosteric site into perspective. This review summarises the patents filed in the three year period to June 1999.

• anxiolytic
• benzodiazepine recognition site
• cognition enhancement
• GABAA receptor
• hypnotic