The continuation of AREA NS038444, which began in June 1999 and is scheduled to end May 2005, is requested. Significant progress has been made towards the central goal of the program, and this application outlines plans for further hypothesis-driven structure-based drug design studies which use isoxazole chemistry developed in our labs. 1. NMDA and AMPA are sub-types of glutamate receptors which are involved with learning, memory and are affected by aging. We propose to further explore the application of our catalytic asymmetric synthesis [reference 1] to prepare ligands that bind to, and to distinguish between, these GluR subtypes. 2. The Glutamate transporters are important in the glutamate-glutamine cycle, and recent preliminary Structure Activity Relationship (SAR) data from the collaboration between Dr. Richard Bridges (University of Montana) and our lab indicates a distinction between the AMPA glutamate receptor and the system Xc- transporter, which we may be able to exploit using our synthetic methodology to develop binding selectivity. Therefore, the synthesis of ligands to further delineate selectivity between these glutamate binding proteins is proposed. 3. Study of the conformational dynamics of the intact receptor and transporter would be facilitated by access to spectroscopic probes. We propose to prepare molecules to spectroscopically study the glutamate receptor and transporter system Xc-. We have reported very encouraging progress towards the first aim, observed exciting preliminary findings for the second, and present hypothesis-driven, molecular-target-based design towards all of our endeavors. And also relevant to the special considerations for the AREA program, our research group has had a significant positive impact on the participation of University of Idaho students in research. ? ?
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