The major objective of this proposal is to design, synthesis and evaluate redox-based chemical delivery systems (CDS) for neurotrophomodulators (NTM), to achieve brain-enhanced delivery of these NTM's for the treatment of the cognitive decline associated with Alzheimer's disease. The CDS to be used is the redox-based dihydrpyridine yields pyridinium ion system which is covalently attached to the active drug. The dihydropyridine moiety enhances lipophilicity and its oxidation in the brain to the charged, quaternary pyridinium ion serves to lock the drug in the brain. The NTM for which brain-directed CDS's would be attached are 4-methylcatechol; catecholamines and catecholamine analogues; the beta-adrenergic agonist, isoproterenol and terbutaline; novel catechol mimics including methylated derivatives of 2-hydroxy-pyridone-1-oxide; and finally estradiol. Each of these NTM-CDS's would be subjected to in vitro evaluation of their physicochemical properties (lipophilicity, oxidative stability and the degree of protein binding) and in vitro rates of oxidation and hydrolysis. Compounds which show appropriate in vitro characteristics would then be evaluated for their in vivo distribution to brain and peripheral tissues. Those NTM-CDS's which exhibit brain- enhanced delivery and sustained release of the active drug would be assessed for their efficacy in stimulating nerve growth factor (NGF) synthesis and release in cortex and hippocampus. Those NTM-CDS which are delivered to and release NTM in the brain and stimulate secretion of NGF would be further evaluated for their efficacy in enhancing plasticity of cholinergic neurons in animal models for cholinergic hypofunction. High affinity choline uptake, choline acetyltransferase activity and acetylcholine synthesis would be evaluated for their efficacy in enhancing memory in tests of passive avoidance and active avoidance. The most promising of the NTM-CDS's would be synthesized in quantities sufficient to conduct animal toxicity tests. Collectively, the studies described should provide a thorough evaluation of the potential use of NTM-CDS in the treatment of the cognitive decline of Alzheimer's disease.
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