Brain-specific benzodiazepine receptors and putative endogenous benzodiazepine-like compounds

The recent demonstration of high-affinity binding sites for the benzodiazepines in the mammalian CNS has provided new information on the mechanism of action of this important class of drugs. The presence of these binding sites has prompted studies on their pharmacological and physiological significance, including attempts at isolating an endogenous ligand. The results presented here support the pharmacological importance of these binding sites as receptors, since there is a highly significant correlation between the occupation of these sites by various benzodiazepines and their clinical effects. Our results further support the physiological significance of the benzodiazepine receptor since brain-specific receptors can be demonstrated in the intact animal under physiological conditions. The isolation of a number of substances from bovine brain that competitively inhibit 3H-diazepam binding to synaptosomal membranes suggests the presence of an endogenous ligand. Two of these substances have been identified as the purines inosine and hypoxanthine. Pharmacological studies of these purines suggest that they may have diazepam-like effects in vivo. These results support the existence in brain of endogenous benzodiazepine-like compounds that could normally be involved in ameliorating anxiety and (or) seizure activity.