Inhibitory effect on 3H-diazepam binding and potentiating action on GABA of ethyl loflazepate, a new minor tranquilizer.
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概要
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A new benzodiazepine compound, ethyl loflazepate (ethyl-7-chloro-2, 3-dihydro-5-(2-fluorophenyl)-2-oxo-1H, 1, 4-benzodiazepine-3-carboxylate; CM-6912) was studied using in vitro experimental systems for its displacement activity on <SUP>3</SUP>H-diazepam binding to the synaptosomal membrane fraction of rat cerebrum and potentiating action on GABA. CM6912 inhibited the specific binding of <SUP>3</SUP>H-diazepam by 25%, 75% and 90% at concentrations of 0.01 μM, 0.1 μM and 1 μM, respectively, while its metabolites CM6913 and CM7116, at 0.1 μM, completely inhibited the binding. Concentrations for 50% inhibition (IC50) were 25 nM for CM6912, 3.2 nM for CM6913 and 1.4 nM for CM7116. These results suggest that the metabolite CM7116 is stronger than its parent compound in displacing the <SUP>3</SUP>H-diazepam binding, and they also suggest that the long-lasting anti-anxietic action of CM6912 might be due to the in vivo formation of CM7116. CM6912, CM7116 and diazepam potentiated the suppressive action of GABA on spontaneous spikes of Purkinje cells in guinea pig cerebellar slices in a dose-dependent manner. Concentrations for 50% suppression (IC50) were 96.0 μM for GABA alone, 75.0 μM for GABA plus diazepam (5 μM), 78.9 μM for GABA plus CM6912 (5 μM) and 60.8 μM for GABA plus CM7116 (5 μM). These findings suggest that CM6912 and CM7116 may potentiate the postsynaptic inhibitory action of GABA in a manner similar to and probably more strongly than diazepam.
- 公益社団法人 日本薬理学会の論文
著者
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NAMIMA Misako
Department of Pharmacology, National Defense Medical College
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Sakai Yutaka
Department Of Information And Computer Sciences Faculty Of Engineering Saitama University
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