The proposed project is aimed at developing a general method for specific and/or enhanced delivery to the brain of a variety of biologically active agents, endogenous bioactive compounds and drugs, and to achieve sustained brain-specific delivery of these agents by affecting their bidirectional movement in and out of the brain, using dihydropyridine pyridinium salt-type redox carrier systems. Based on the direct (analytical) and pharmacological evidence for the brain-specific delivery of dopamine coupled to a redox CDS (chemical delivery sstem), it is proposed to investigate CNS delivery of other important neurotransmitters, like GABA and serotonin (via the precursors like tryptophan and 5-OH-tryptophan). The effect of these will also be investigated on the brain concentrations of other CNS amines, neurotransmitters and their metabolites. HPLC and GC-MS will be employed. Detailed studies of the influx of the lipid-soluble form and efflux of the charged species, including the carrier moieties formed after cleavage of the quaternary pyridinium carrier-drug linkage, will be undertaken. The structural requirements for optimum delivery and limitations of the bidirectional movement will be established. Ne redox-type carrier systems are proposed to be investigated to allow more facile brain release of some of the amine containing bioactive compounds. Based on a very prolonged (24 days) activity of brain-specific estradiol-redox carrier CDS, detailed pharmacodynamic approaches are proposed to evaluate the brain-specific delivery of gonadal steroids attached to redox CDS's. Two different directions for the delivery of neuropeptides and related compounds are proposed. One is using the general redox CDS approach. Varios carriers will be employed. The new trigonle-glycine combined carrier has special importance, as it requires peptide link cleavage. The second main direction involves design and evaluation of novel brain-specific peptide analogs based on some recently designed new amino acids. Among the therapeutic drug classes, it is proposed to focus on anticonvulsants and antitumor agents. The proposed approaches include design and testing for delivery of currently used agents and new analogs, which have the intrinsic brain-specific properties. In vitro studies of all of the redox systems will precede their in vivo evaluation: distribution into various organs, metabolism and release kinetics. Pharmacological evaluation of the best systems will be undertaken. Theoretical studies of the energetic and electronic processes will be continued.
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