Japanese Journal of Pharmacology 1985-04-01

Inhibitory effect on 3H-diazepam binding and potentiating action on GABA of ethyl loflazepate, a new minor tranquilizer.

Y Sakai, M Namima

Index: Jpn. J. Pharmacol. 37(4) , 373-9, (1985)

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Abstract

A new benzodiazepine compound, ethyl loflazepate (ethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H,1,4- benzodiazepine-3-carboxylate; CM6912) was studied using in vitro experimental systems for its displacement activity on 3H-diazepam binding to the synaptosomal membrane fraction of rat cerebrum and potentiating action on GABA. CM6912 inhibited the specific binding of 3H-diazepam by 25%, 75% and 90% at concentrations of 0.01 microM, 0.1 microM and 1 microM, respectively, while its metabolites CM6913 and CM7116, at 0.1 microM, 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 3H-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 microM for GABA alone, 75.0 microM for GABA plus diazepam (5 microM), 78.9 microM for GABA plus CM6912 (5 microM) and 60.8 microM for GABA plus CM7116 (5 microM). 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.