Molecular aspects of the action of benzodiazepine and non-benzodiazepine anxiolytics: a hypothetical allosteric model of the benzodiazepine receptor complex.

The availability of radiolabeled benzodiazepines has resulted in the identification of high affinity receptors in the central nervous system for this class of psychotherapeutic agent which are linked to recognition sites for the inhibitory neurotransmitter, GABA. Evaluation of new, synthetic compounds in the benzodiazepine radioligand binding assay has resulted in the identification of nine classes of non-benzodiazepine putative anxiolytic agents, some of which may be more anxioselective than the benzodiazepines. At least three and possibly five subclasses of benzodiazepine receptor have been identified in mammalian tissues using radioligand binding assays. The possibility exists that one of these receptor subclasses may mediate the anxiolytic effects of the benzodiazepines while the remainder may be involved in the mediation of the sedative, ataxic and anticonvulsant properties associated with benzodiazepine-like agents. Several endogenous ligands for the benzodiazepine receptor(s) have been postulated. These include various proteins and peptides, purines and the beta-carbolines. This latter group, which competitively antagonizes the pharmacological and biochemical effects of the benzodiazepines, has the highest affinity for the benzodiazepine receptor of all compounds thus far examined; however, none of these compounds has been conclusively identified as the endogenous ligand akin to the enkephalins and endorphins at the opiate receptor. The majority of available evidence would indicate that the endogenous ligand for the benzodiazepine receptor(s) is an antagonist of the benzodiazepines and other putative anxiolytic agents.