Larionov V. Pharmacological analysis of the blood-brain barrier permeability in the strategy of novel neuroavailable substances development

The dissertation is dedicated to the development of complex strategy for blood- brain barrier permeability studying for chemicals with attention to physics-chemical and biochemical factors, estimation and prediction of their neuroavailability on the base of interrelationships between structure, physics-chemical properties and pharmacokinetic parameters. The comparative analysis for neuroavailability parameter for probe samples of intercellular (aliphatic alcohols) and cellular (1.4-benzdiazepine derivatives) simple diffusion as well as cellular active transport (aliphatic acids and aminoacids) markers. With methanol and ethanol their interinfluence on the common simple intercellular diffusion had been shown. Determined the butyrate transport selectivity through brain-blood ratio in vivo. The possibility of brain-blood ratio permeability estimation on the base of pharmaco-toxicological methods was shown. For prodrugs, that undergo intracerebral biotransformation (levana and its active metabolite (3-oxyphenazepam) the ability of pharmacological spectrum changing had been justified. Using computation method of 2D modeling the computer models for neuroavailability prediction were developed.