Although the etiology of Alzheimer's disease is not known, it is clear that the clinical course is associated with a progressive neuronal dysfunction and loss of neurons. Intracellular calcium ([Ca2+]i) levels are of fundamental importance in neuronal growth as well as neuronal degeneration and death. It is hypothesized that neuronal [Ca2+]i is regulated in part by phosphoinositides and inositol polyphosphates and that modulation of these intracellular signal pathways could protect cells and improve vitality. A unique series of bioisosteres of inositol, inositol polyphosphates and phosphatidylinositols will be developed to blunt excessive changes in intracellular calcium. Various bioisosteres of inositol particularly fluoro-inositol compounds, inositol phosphate bioisosteres including nitro and carboxyl mimics of inositol-1,4,5 trisphosphate [Ins(1,4,5)P3] and Inositol-1,3,4,5 tetrakisphosphate- [Ins(1,3,4,5)P4] second messengers and bioisosteres of phosphoinositides will be synthesized. Initial screens will help identify structure activity relationships of compounds for Ins(1,4,5)P3 receptors, Ins(1,3,4,5)P4 receptor sites and for calcium release and/or sequestration responses. Additional studies will investigate the effects of compounds on phosphoinositide hydrolysis and inositol polyphosphate metabolism. Promising compounds will be further analyzed in cellular systems for effects on the synthesis of phosphoinositides, receptor stimulated formation of inositol polyphosphate second messengers, changes in intracellular calcium [Ca2+]i and cellular toxicity to agents causing large increases in intracellular calcium. At the final stages brain slice preparations treated with drug first in vitro and subsequently following in vivo treatment of rats will be used to evaluate the efficacy of promising compounds on changes in hippocampal function including: long-term potentiation, the calcium activated after hyperpolarization [Ca2+-AHP], neurotransmitter stimulated inositol polyphosphate formation and passive avoidance trails. These studies may lead to new strategies and new classes of compounds for the treatment of Alzheimer's disease and may help unravel the various facets of inositol signaling known to be of fundamental importance in neuronal growth, plasticity and vitality. The study of inositol bioisostere modulation of phosphoinositide regulation of [Ca2+]i will clarify the process of calcium homeostasis and hopefully result in a beneficial therapy for Alzheimer's disease.
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