Ethyl loflazepate: a prodrug from the benzodiazepine series designed to dissociate anxiolytic and sedative activities.

Ethyl loflazepate (Victan) is an original 1,4-benzodiazepine (BZD) being used as a potent, nonsedative, minor tranquillizer. Ethyl loflazepate was designed to be a prodrug that would gradually release within the organism an active 1,4-BZD. It was hypothesized that this type of pharmacokinetic profile would dissociate anxiolytic from sedative activities. Previously published pharmacokinetic studies performed in rats, baboons and humans have confirmed that ethyl loflazepate gradually releases in the plasma an active 1,4-BZD, descarboxyloflazepate. In the present study, the activity of ethyl loflazepate and its main plasmatic metabolites were examined in rodent models predictive of anxiolytic, anticonvulsant, myorelaxant and sedative properties. The activities of ethyl loflazepate and its metabolites were compared to those of reference BZDs: diazepam, bromazepam, nitrazepam, flunitrazepam, lorazepam, clorazepate. Ethyl loflazepate and its metabolites revealed the typical profile of activity of minor tranquillizers. The activity of ethyl loflazepate was long-lasting. The overall anxiolytic potency of ethyl loflazepate was similar to that of diazepam but ethyl loflazepate appeared to be less sedative than diazepam. Thus in the approach-avoidance conflict procedure in rats the threshold anxiolytic doses were 1 and 2 mg/kg i.p. for ethyl loflazepate and diazepam, respectively, whereas the threshold sedative doses were 16 and 8 mg/kg i.p., respectively. In vitro ethyl loflazepate exhibited a weak affinity for the BZD receptor site. In vivo ethyl loflazepate displaced [3H]-flunitrazepam from mice brain membranes with a potency comparable to that of lorazepam. In vitro, descarboxyloflazepate, the main plasmatic metabolites of ethyl loflazepate, revealed a 4-fold greater affinity for the BZD receptor than diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)