The proposed project is aimed at developing a new and general method for site specific and enhanced brain delivery of drugs by affecting their bidirectional movement in and out of the brain, based on a bioreversible dihydropyridine pyridinium salt type redox chemical delivery system. The basic concept was demonstrated by the enhanced and sustained brain delivery of phenylethylamine using a trigonelline dihydrotrigonelline type redox system. Further support was obtained by the dramatic increase in the brain delivery of the quaternary compound, berberine, as dihydroberberine. The project is aimed to achieve brain-specific and sustained delivery of a variety of bioactive agents such as tyramine, dopamine, L-DOPA; small peptides, such as enkephalins; steroid hormones, like estradiol, testosterone, 17Alpha-ethynyl testosterone; antitumor agents of the fused polyheteroaromatic quaternary salt types; muscle relaxants; major tranquilizers from the class of benzodiazepines; memory enhancing agents; etc. It is proposed to develop a flexible arsenal of redox delivery systems, which can be adjusted to specific cases. A further major objective is to gain basic information about the transport processes (active and passive) of, and enzymatic activities in, the blood-brain barrier. It is expected to achieve significant reduction in systemic and/or brain toxicities of a number of important drugs. It is expected to obtain information about various processes specific to the function of the brain. The proposed project involves synthesis of the redox-carrier derivatives of the various above drugs (for example the 17-ester of testosterone with N-methylnicotinic acid, the corresponding 1, 4-dihydropyridine derivative); physical-chemical studies of the individual carrier-drug redox systems; in vitro kinetics of conversion of the dihydrocarrier system [D-DHC] to the quaternary derivative [D-QC]+ in various biological fluids (brain homogenate, blood, liver, etc.); in vitro kinetics of the [D-QC]+=[D]+[QC]1+ delivery process; in vivo brain delivery studies of [D-QC]+ via the [D-DHC]; systemic and brain pharmacokinetics of [D-QC]+ vs. [D-DHC] and the release of [D]; relevant pharmacological studies; detailed bidirectional transport studies of the various species involved, in and out of the brain; whole body distribution studies; and theoretical studies of the energetic and electronic processes involved in the redox systems used.
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