Ligands to study the glutamate receptor and transporters

研究谷氨酸受体和转运蛋白的配体

• 批准号: 7029159
• 负责人: Nicholas R. Natale
• 金额: $ 6.73万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029159
• 关键词: AMPA receptors; NMDA receptors; catalyst; chemical structure function; chemical synthesis; conformation; fluorescent dye /probe; genetic strain; glutamate transporter; glutamine; isoxazoles; laboratory mouse; ligands; protein structure function; receptor binding; spectrometry

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.

描述（由申请人提供）：区域NS 038444的延续，始于1999年6月，计划于2005年5月结束，要求。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，它们参与学习、记忆并受衰老影响。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，以制备结合并区分这些GluR亚型的配体。2.谷氨酸转运蛋白在谷氨酸-谷氨酰胺循环中很重要，最近来自Richard Bridges博士（蒙大拿大学）和我们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-转运蛋白之间的区别，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，提出了合成配体以进一步描绘这些谷氨酸结合蛋白之间的选择性。3.研究的构象动力学的完整的受体和转运蛋白将有助于获得光谱探针。我们建议制备分子光谱研究谷氨酸受体和转运系统XC-。我们已经报告了非常令人鼓舞的进展，实现第一个目标，观察到令人兴奋的初步结果，第二，目前的假设驱动，分子靶向设计对我们所有的努力。与区域计划的特殊考虑有关，我们的研究小组对爱达荷州大学学生参与研究产生了重大的积极影响。