Stimulus Properties of Benzodiazepines: Correlations with Binding Affinities, Therapeutic Potency, and Structure Activity Relationships (SAR)

Using a two-lever operant choice task, rats were trained to discriminate diazepam (3.0 mg/kg) from saline under a fixed-ratio 10 (FR10) schedule of reinforcement. Once the discrimination was learned, generalization studies were conducted using various doses of 17 benzodiazepine derivatives. The diazepam stimulus generalized in a dose-related manner to each of these compounds. ED50 values were compared with available data on displacing affinities (Ki values) for tritiated diazepam brain binding in man, and with human therapeutic potency. A significant correlation (r = 0.88, n = 9) was found between benzodiazepine binding affinities and ED50 values derived from the diazepam stimulus generalization assay. A significant correlation (r = 0.92, n = 10) was also found between drug discrimination ED50 values and human therapeutic potencies. Finally, the benzodiazepine structure activity relationships generated from the drug discrimination studies closely paralleled the known structure activity relationships for these agents. The results provide further evidence that benzodiazepines exert their pharmacological effects through an interaction with benzodiazepine receptors.