Pharmacodynamics of Interaction between Propoxazepam and a GABA-Benzodiazepine Receptor-Ionofor Complex
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Effects of a propyloxy derivative of 1.4-benzodiazepine, propoxazepam, on GABA-benzodiazepine receptor complexes (GABA RCs) were examined in vitro and in vivo. The parameters of propoxazepam binding to synaptosomes from the rat brain were estimated in vitro. The Ki constant for inhibition of [3H] flumazenil binding by this agent was 3.5 ± 0.3 nM, on average. Considering the value of the GABA shift (1.9), propoxazepam can be considered as GABA-RC full agonist. On the model of picrotoxin-induced seizures in vivo, the propoxazepam average effective dose was estimated as 4.1 ± ± 0.21 mmol/kg. It was found that the parameters of myoclonic components (latent period of the onset of myoclonic seizures and their number), as well as death time of the tested animals, characterize adequately an anticonvulsant action of propoxazepam of picrotoxin-induced seizures in mice. Competitive interaction with picrotoxin is the possible mechanism of these effects at the level of GABAARCs. Significant deviations from a competitive model of monomolecular and cooperative binding of the agent at the receptor level have been found.
Keywordspropoxazepam picrotoxin GABA-benzodiazepine receptor complex affinity anticonvulsant effect
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