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Electrophysiological aspects of benzodiazepine antagonists ro 15 1788 flumazepil and ro 15 3505 ethyl 7 chloro 5 6 dihydro 5 methyl 6 oxo 4h imidazo 1 5 a 1 4 benzodiazepine 3 carboxylate


, : Electrophysiological aspects of benzodiazepine antagonists ro 15 1788 flumazepil and ro 15 3505 ethyl 7 chloro 5 6 dihydro 5 methyl 6 oxo 4h imidazo 1 5 a 1 4 benzodiazepine 3 carboxylate. British Journal of Clinical Pharmacology 18(4): 541-548

The comparative action of 2 specific benzodiazepine antagonists, Ro 15-1788 and Ro 15-3505, was examined in 6 healthy volunteers. Medication was given i.v. in a double-blind cross over pattern, and EEG was recorded throughout each experimental session. Ten min after the injection of one of the antagonists or placebo, midazolam was injected in incremental doses until first signs of drowsiness appeared in the EEG. The EEG was computer analyzed, using adaptive segmentation and time-dependent clustering. Continuous power profiles for various frequency bands, as well as power ratios for the physiological frequency bands (e.g., sigma/alpha power ratio) were generated. Sigma/alpha power ratio was the most sensitive parameter detecting early effects of midazolam on the EEG signal, thus enabling a semi-quantitative titration of the antagonists by midazolam. Ro 15-1788 in doses of 5 mg i.v. was counteracted on average by 7.3 mg midazolam. From the EEG analysis, Ro 15-3505 was at least 4-5 times more potent than Ro 15-1788. [Such selective benzodiazepine antagonists have a highly potential use in controllability of anesthesia and the post-operative period, and as antidotes in cases of overdosage of benzodiazepines.].

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Codding P.W.; Muir A.K.S., 1985: Molecular structure of ro 15 1788 ethyl 8 fluoro 5 6 dihydro 5 methyl 6 oxo 4h imidazo 1 5 a 1 4 benzodiazepine 3 carboxylate and a model for the binding of benzodiazepine receptor ligands structural identification of common features in antagonists. Ligands that bind to the benzodiazepine receptor have 3 possible effects. The ligand can be an agonist and reduce anxiety, an antagonist and have no biological effect or an inverse agonist and promote convulsions. This receptor complex is unique i...

Schweri M.; Cain M.; Cook J.; Paul S.; Skolnick P., 1982: Blockade of 3 carbomethoxy beta carboline induced seizures by diazepam and the benzodiazepine antagonists ro 15 1788 ethyl 8 fluoro 5 6 dihydro 5 methyl 6 oxo 4h imidazo 1 5 alpha 1 4 benzodiazepine 3 carboxylate and cgs 8216 2 phenyl pyrazolo 4 3 c quinolin 3 5h one. The benzodiazepine antagonists Ro 15-1788 and CGS 8216 blocked the clonic and tonic convulsions elicited by 3-carbomethoxy-.beta.-carboline (.beta.-CCM). The PD50 [median protective dosage] values for Ro 15-1788, CGS 8216 and diazepam were: 2.0, 0...

Darragh A.; Lambe R.; Scully M.; Brick I.; O'boyle C.; Downie W.W., 1981: Investigation in man of the efficacy of a benzodiazepine antagonist ro 15 1788 ethyl 8 fluoro 5 6 dihydro 5 methyl 6 oxo 4h imidazo 1 5 a 1 4 benzodiazepine 3 carboxylate. In a randomized double-blind crossover study, Ro 15-1788, an imidazodiazepine derivative, was shown by psychometric evaluation to antagonize the central benzodiazepine effects of Ro 11-3128 (3-methylclonazepam) in healthy male volunteers when both...

Klotz U.; Ziegler G.; Reimann I.W., 1984: Pharmacokinetics of the selective benzodiazepine antagonist ro 15 1788 ethyl 8 fluoro 5 6 dihydro 5 methyl 6 oxo 4h imidazo 1 5 a benzodiazepine 3 carboxylate in man. European Journal of Clinical Pharmacology 27(1): 115-118

Bonetti E.P.; Pieri L.; Cumin R.; Schaffner R.; Pieri M.; Gamzu E.R.; Mueller R.K.M.; Haefely W., 1982: Benzodiazepine antagonist ro 15 1788 ethyl 8 fluoro 5 6 dihydro 5 methyl 6 oxo 4h imidazo 1 5 a 1 4 benzodiazepine 3 carboxylate neurological and behavioral effects. In neurological and behavioral studies in mice, rats, dogs and squirrel monkeys, the imidazobenzodiazepinone Ro 15-1788 acted as a potent benzodiazepine antagonist. The antagonistic activity was both preventive and curative and seen at doses at wh...

Chiu T.H.; Rosenberg H.C., 1983: Conformational changes in benzodiazepine receptors induced by the antagonist ro 15 1788 ethyl 8 fluoro 5 6 dihydro 5 methyl 6 oxo 4h imidazo 1 5 a 1 4 benzodiazepine 3 carboxylate. The binding kinetics of [3H]Ro 15-1788, a selective benzodiazepine receptor antagonist, to synaptosomal membranes of rat cerebral cortices were studied. [3H]Ro 15-1788 binds with high affinity (dissociation constant, 0.53 nM) to a single class of...

Brick I., 1983: Absence of central effects in man of the benzodiazepine antagonist ro 15 1788 ethyl 8 fluoro 5 6 dihydro 5 methyl 6 oxo 4h imidazo 1 5 a 1 4 benzodiazepine 3 carboxylate. Psychopharmacology: 195

Goeders N.E.; Kuhar M.J., 1985: Benzodiazepine receptor binding in vivo with tritiated ro 15 1788 ethyl 8 fluoro 5 6 dihydro 5 methyl b oxo 4h imidazo 1 5 a 1 4 benzodiazepine 3 carboxylate. In vivo benzodiazepine receptor binding has generally been studied by ex vivo techniques. The conditions where [3H]-Ro 15-1788 labels benzodiazepine receptors [mouse] by true in vivo binding, i.e., where workable specific to nonspecific ratios are...

Cooper S.J., 1982: Specific benzodiazepine antagonist ro 15 1788 ethyl 8 fluoro 5 6 dihydro 5 methyl 6 oxo 4h imidazo 1 5 a1 4 benzodiazepine 3 carboxylate and thirst induced drinking in the rat. Midazolam, a new H2O-soluble benzodiazepine, increased the H2O intake of H2O-deprived rats. The effect was abolished by concurrent treatment with the benzodiazepine antagonist RO15-1788. The lack of effect of RO15-1788 on phenobarbitone-induced hy...

Polc P.; Laurent J P.; Scherschlicht R.; Hafefely W., 1981: Electro physiological studies on the specific benzodiazepine antagonist ro 15 1788 ethyl 8 fluoro 5 6 dihydro 5 methyl 6 oxo 4 h imidazo 1 5 a 1 4 benzodiazepine 3 carboxylate. The imidazobenzodiazepinone derivative, Ro 15-1788 [ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate], the 1st representative of specific benzodiazepine antagonists, was studied electrophysiologically i...