Current antipsychotic drugs fail to produce significant clinical improvement in many patients with schizophrenia and carry liabilities for cognitive function in adults and brain development in younger patients. Moreover, these drugs were not designed to address the neurodevelopmental deficits (e.g., loss of gray matter) that underlie this disease. Therefore, a new treatment paradigm has been proposed, termed neuroenhancement, which is aimed at optimization of glucose metabolism and functional activity in neurons. The long-term goal of this research is to develop high-potency, small molecule drugs that enhance neuronal growth and viability. The lead compound for this approach is olanzapine, which is unique among the antipsychotic drugs in promoting neuronal survival. The positive effects of olanzapine on cells may stem from activation of signaling pathways, including Akt and mitogen-activated protein kinases (MAPK), such as ERK and p38. Initial structure-activity relationship (SAR) analysis and chemical database searches led to the identification of analogs of olanzapine with similar biological properties. Research will now focus on the following Specific Aims: (1) to profile antipsychotic drugs and hits from screening with respect to activation of key signaling pathways, (2) to confirm positive effects of neuroenhancing agents on glucose metabolism, and (3) to refine the SAR for neuroenhancement. Drugs and compounds will be evaluated for protection of rat and human neuronal cell lines, from various insults. Effects on cell viability will be determined with several independent assays. The drugs will be evaluated for activation of kinases (Akt, ERK, p38 and Src) by westem blot analysis, and for downstream effects, including upregulation of the surface expression of glucose transporters (GLUTs), glucose transport and metabolism. The role of particular kinases in the response will be established by addition of specific inhibitors. Pharmacophore models will be generated to guide automated searches of chemical databases for analogs that will be tested for biological activity. Hits will be evaluated for activation of kinases and effects on glucose transport to confirm the mechanism of action. The pharmacophore model will be revised after each round of screening with additional input from molecular modeling. Ultimately, these studies may lead to the development of new drugs for early intervention in schizophrenia. ? ? ?
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