P-185) Ex vivo inhibition by flutoprazepam of 3H-flunitrazepam binding to mouse brain homogenate.

Abstract

Flutoprazepam (FPZ), a new antianxiety drug of benzodiazepine class, was found to be more active in preventing pentetrazole induced convulsion than predicted from the Ki value obtained from binding studies in vitro. Several benzodiazepines are extensively biotransformed in vivo, giving rise to active metabolites. This complicates any attempt to correlate pharmacological effects with in vitro potencies, taking into account that benzodiazepines are metabolized differently in various animal species. Therefore, we studied the ability of FPZ and its metabolites, N-desalkyl-FPZ and N-desalkyl-3-OH-FPZ, to inhibit 3H-flunitrazepam (FNZ) binding to mouse brain ex vivo and compared it with the potencies for anti-pentetrazole activity. FPZ and its metabolites inhibited the specific 3H-FNZ binding dose-dependently as diazepam (DZP), prazepam (PZP), nitrazepam (NZP) and chlordiazepoxide (CZP) did. With regard to ID50 (mg/kg, p.o.), the potency of FPZ was about 3-6 times higher than those of DZP, NZP and PZP and was about 80 times higher than that of CZP. Two metabolites of FPZ were 1-2 times as active as FPZ. The correlation between the ED50 values for anti-pentetrazole activity and the ID50 values was statistically significant (r=0.929). These results suggest that the two metabolites of FPZ participate partly in the pharmacological effect of FPZ.