Ligands to study the glutamate receptor and transporters

描述(申请人提供)：申请延续NS038444地区，该地区于1999年6月开始，计划于2005年5月结束。该计划的中心目标已经取得了重大进展，该申请概述了进一步的假设驱动的基于结构的药物设计研究的计划，这些研究使用了我们实验室开发的异恶唑化学。1.NMDA和AMPA是谷氨酸受体的亚型，与学习、记忆有关，受衰老的影响。我们建议进一步探索我们的催化不对称合成[参考文献1]的应用，以制备与这些GluR亚型结合并区分它们的配体。2.谷氨酸转运体在谷氨酸-谷氨酰胺循环中是重要的，最近由蒙大拿大学的Richard Bridges博士和我们的实验室合作的初步结构活性关系(SAR)数据表明AMPA谷氨酸受体和系统XC-转运体之间的区别，我们可能能够利用我们的合成方法来开发结合选择性。因此，建议合成配体来进一步描述这些谷氨酸结合蛋白之间的选择性。3.使用光谱探针有助于研究完整受体和转运蛋白的构象动力学。我们建议制备分子来对谷氨酸受体和转运蛋白系统XC-进行光谱研究。我们已经报告了朝着第一个目标非常令人鼓舞的进展，观察到第二个目标令人兴奋的初步发现，并针对我们所有的努力提出了假设驱动的、基于分子靶标的设计。我们的研究小组对爱达荷大学的学生参与研究产生了重大的积极影响，这也与AREA计划的特殊考虑有关。

DESCRIPTION (provided by applicant): 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.