Benzodiazepine receptor antagonists: Possible uses in the treatment of neuropsychiatric disorders

Abstract

The receptor to which benzodiazepine hypnosedatives and anticonvulsants bind was discovered and characterised in the late 1970s. Agonists and inverse agonists that act at various sites within the receptor complex have been identified. In addition, antagonists of the benzodiazepine receptor have been synthesised. At present, flumazenil is the only agent of this class that is available clinically. Flumazenil has well documented benefits in the treatment of hepatic encephalopathy and benzodiazepine overdose. The drug has also been studied as a potential treatment for neuropsychiatric illnesses in which dysfunction of the γ-aminobutyric acid (GABA)ergic system is implicated as a causal factor. Potential therapeutic benefits are suggested in benzodiazepine tolerance and withdrawal, benzodiazepine-related amnesia, epilepsy, sleep disorders, cognitive disorders and idiopathic recurrent stupor. In contrast, no clear benefits have been found in alcoholism, anxiety and movement disorders. Flumazenil induces few adverse effects, and so represents a promising tool for pharmacological investigations of the GABAergic system and for imaging of the benzodiazepine receptor. As an imaging agent it has been used for quantification of the receptor, and as a neuronal marker in epilepsy and cerebral ischaemia.