title: In vitro and ex vivo inhibition by flutoprazepam of [3H]flunitrazepam binding to mouse brain receptors.
abstract: The ability of flutoprazepam, a new antianxiety drug of the benzodiazepine class, to inhibit [3H]flunitrazepam binding to mouse brain receptors was investigated in vitro and ex vivo (measurement of [3H]flunitrazepam binding in vitro after in vivo treatment of animals with unlabelled drugs). The Ki values for [3H]flunitrazepam binding in vitro were as follows: flutoprazepam (13.0 nM), diazepam (2.7 nM), nitrazepam (5.3 nM), prazepam (68.5 nM) and chlordiazepoxide (234 nM). Two metabolites of flutoprazepam, N-desalkyl-flutoprazepam (Ki = 3.1 nM) also inhibited [3H]flunitrazepam binding in vitro with higher potencies than that of flutoprazepam. Flutoprazepam was found to be more active in inhibiting [3H]flunitrazepam binding ex vivo and in preventing pentetrazol convulsions than predicted from Ki values. The ID50 values for inhibiting [3H]flunitrazepam binding ex vivo were 0.32 mg/kg, p.o. (flutoprazepam), 0.89 mg/kg, p.o. (diazepam), 0.94 mg/kg, p.o. (nitrazepam), 1.98 mg/kg, p.o. (prazepam) and 23.3 mg/kg, p.o. (chlordiazepoxide), respectively. The correlation between ID50 values ex vivo and ED50 values for preventing pentetrazol convulsions was highly significant (r = 0.929). These results suggest that flutoprazepam can exert its pharmacological activities by itself and that two metabolites also play an important role in the effects of flutoprazepam in vivo.
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants; D001570:Benzodiazepinones / Q000494:pharmacology*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D005445:Flunitrazepam / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011963:Receptors, GABA-A
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001570:Benzodiazepinones; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; C029163:flutoprazepam; D005445:Flunitrazepam; D010433:Pentylenetetrazole