Pharmacological studies with quazepam, a new benzodiazepine hypnotic.

Abstract

7-Chloro-1-(2,2,2-trifluoroethyl)-5-(o-fluorophenyl)-1, 3-dihydro-2H-1,4-benzodiazepine-2-thione (Sch 16134, quazepam) demonstrated high safety and effective hypnotic properties. Toxicity of quazepam in mice was extremely low at the largest doses administered of 5000 mg/kg p.o. and 1370 mg/kg i.p. as compared to LD50 values for flurazepam of 756 (635-889) mg/kg p.o. and 254 (234-280) mg/kg i.p. In cats, quazepam did not produce overt toxicity even at the highest dose administered, 1000 mg/kg p.o., whereas death occurred after the administration of flurazepam at a median dose of 250 mg/kg p.o. In addition, flurazepam produced central excitation and convulsions. Quazepam did not affect hemodynamic parameters in conscious dogs and anesthetized cats. Autonomic functions were virtually unaffected by the drug in anesthetized cats. In interaction studies in mice, quazepam did not interact with cimetidine while it potentiated the sedative activity of alpha-methyldopa, ethanol and propranolol. The CNS depressant properties of quazepam were further investigated by studying its effects on spontaneous motor activity in mice and EEG pattern in immobilized cats. In mice, quazepam reduced locomotor activity at doses which did not impair motor coordination thus differing from flurazepam which did. In the EEG study, quazepam produced a slow wave EEG pattern comparable to that of physiological sleep, while flurazepam induced a similar EEG activity which alternated with a fast frequency pattern of moderate amplitude. Quazepam also showed potent anticonvulsant activity. These results suggest that quazepam is likely to be a safe and effective sleep-promoting agent.