Interaction of benzodiazepines with central nervous glycine receptors: possible mechanism of action.

Interaction of 21 benzodiazepines with the glycine receptor in the brainstem and spinal cord of rat have been evaluated in terms of their displacement of [(3)H]strychinine binding. The rank order of potency of the 21 drugs in displacing specific [(3)H]strychinine binding correlates (p < 0.005) with their rank order of potency in a vareity of pharmacological and behavioral tests in humans and animals that predict clinical efficacy. There is a 50-fold variation in potency of the series of benzodiazepines with mean effective dose (ED(50)) values ranging from 19muM to > 1000 muM. Diazepam (Valium(R)) and chlordiazepoxide (Librium(R)) have ED(50)'s of 26 muM and 200 muM, respectively, whereas the ED(50) for glycine is 25 muM. The inhibitory effects of 10 of the agents in two other central nervous system membrane receptor assays, for the opiate receptor and the muscarinic cholinergic receptor, do not correlate with any of the in vivo pharmacologic and behavioral tests. The benzodiazepines may exert their antianxiety, anticonvulsant and muscle-relaxant effects by mimicking the effects of the neurotransmitter glycine at its central nervous system receptor sites.