Correlations Among Minimal Neurotoxicity, Anticonvulsant Activity, and Displacing Potencies in [3H]Flunitrazepam Binding of Benzodiazepines

Abstract

Five clinically available 1,4-benzodiazepines (BDZ) (chlordiazepoxide, diazepam, oxazepam, nitrazepam and clonazepam) and 4 investigational 1,4-BDZ [BDZ I, BDZ II, BDZ III and BDZ IV] were tested in vivo [in mice] for minimal neurotoxicity (TD50) and for ability to obtained seizures (ED50) induced by a battery of 5 well-standardized procedures (maximal electroshock, strychnine, pentylenetetrazol, bicuculline and picrotoxin). These BDZ were also tested in vitro as inhibitors of [3H]flunitrazepam binding to BDZ receptors. The results with each of the 6 in vivo tests were compared with those with the in vitro receptor binding test, and the correlation coefficients (r) were calculated. There was a high correlation between Ki derived from BDZ binding studies and the TD50 values (r = 0.882) and the pentylenetetrazol ED50 values (r = 0.946). There was also good correlation between ED50 values of BDZ effective by the bicuculline and picrotoxin tests and their Ki values in the BDZ receptor binding studies (r = 0.868 and 0.892, respectively). BDZ I, BDZ II and BDZ IV had Ki values of 1.830, 0.075 and 0.015 .mu.M, respectively, but BDZ I was ineffective in nontoxic doses by the bicuculline and picrotoxin tests, BDZ II by the picrotoxin test, and BDZ IV by the bicuculline test. There was no correlation between the BDZ anticonvulsant potency, determined by either the maximal electroshock or strychnine test, and their inhibitory potency on [3H]flunitrazepam binding to receptor sites. The possible methodological and neurochemical bases for these differences are discussed. Evidently BDZ binding studies can be used to screen BDZ for anticonvulsant activity (selectively for antipentylenetetrazol activity and less selectively for antibicuculline and antipicrotoxin activity), and they complement the conventional in vivo anticonvulsant threshold tests. Therefore, BDZ binding studies can be used in concert with conventional in vivo procedures for the pharmacological differentiation of candidate antiepileptic BDZ.