We quantitatively estimated the permeability of the blood-brain barrier (BBB) for some derivatives of 1,4-benzodiazepine based on their pharmacodynamical characteristics and neuroreceptor properties. As was noted, interactions between benzodiazepine ligands and GABA receptor channels (GABA RCs) are rapidly reversible since these interactions depend on the pharmacokinetic characteristics of the compounds used. Examination of rapidly-reversible effects in experiments on animals was carried out under conditions of intravenous infusion of a convulsive agent (corazole) against the background of injection of agonists of GABA RCs (phenazepam, gidazepam, 3-hydroxyphenazepam, Br-nordiazepam, and levana). A hyperbolic pattern of the concentration-effect dependence for phenazepam, 3-hydroxyphenazepam, and Br-nordiazepam allows one to perform adequate calculations of the corresponding concentrations in the brain under condition where their anticonvulsive action does not exceed 80% of the maximum. Calculated ratios of the brain/blood concentrations differed insignificantly from real values obtained in experiments with the use of radioactive isotope-labeled substances. Estimates of the concentrations of prodrugs (levana and gidazepam) in the brain, when based on their pharmacodynamical indices, are inadequate because metabolites of these agents are more active than these compounds per se.
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Golovenko, N.Y., Larionov, V.B. Pharmacodynamical and Neuroreceptor Analysis of the Permeability of the Blood-Brain Barrier for Derivatives of 1,4-Benzodiazepine. Neurophysiology 46, 199–205 (2014). https://doi.org/10.1007/s11062-014-9429-2
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DOI: https://doi.org/10.1007/s11062-014-9429-2