Ligands to study the glutamate receptor and transporters

说明（由申请人提供）： 请求延续 AREA NS038444，该计划于 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，并受衰老影响。我们建议进一步探索催化不对称合成 [参考 1] 的应用，以制备与这些 GluR 亚型结合并区分的配体。 2. 谷氨酸转运蛋白在谷氨酸-谷氨酰胺循环中很重要，Richard Bridges 博士（蒙大拿大学）和我们实验室合作的最新初步结构活性关系 (SAR) 数据表明 AMPA 谷氨酸受体和 Xc-转运蛋白系统之间存在区别，我们可以使用我们的合成方法来利用它来开发结合选择性。因此，建议合成配体以进一步描述这些谷氨酸结合蛋白之间的选择性。 3. 通过使用光谱探针将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光谱研究谷氨酸受体和转运系统 Xc-。我们报告了第一个目标取得的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、基于分子目标的设计。与 AREA 计划的特殊考虑相关，我们的研究小组对爱达荷大学学生参与研究产生了重大的积极影响。

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.