CLEFT-BINDING NMDA RECEPTOR SUBTYPE ANTAGONISTS

裂口结合 NMDA 受体亚型拮抗剂

• 批准号: 6726133
• 负责人: DANIEL T MONAGHAN
• 金额: $ 25.17万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-06 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6726133
• 关键词: NMDA receptors; Xenopus oocyte; chemical synthesis; glutamates; inhibitor /antagonist; point mutation; protein binding; protein structure function

DESCRIPTION(Adapted from applicant's abstract): NMDA receptors are involved in several critical functions of the CNS such as cellular mechanisms of learning, pain perception, motor patterns, experience-dependent synapse formation, and others. These receptors are also involved in epilepsy, narcotic adaptation, and neuronal cell death following ischemia, head and spinal cord injury, and HIV infection. Presently the roles that the various NMDA receptor subtypes play in these diverse actions are unknown. We propose to develop subtype-selective antagonists to facilitate the study of NMDA receptor subtypes in normal and abnormal CNS function. We propose to develop a new category of NMDA receptor antagonist- "cleft-binding" antagonists. Our previous antagonist development studies, as well as our molecular modeling studies, have lead us to the conclusion that antagonists of greater subtype-selectivity will require large side groups that can interact with the unique amino acid residues that lay outside the primary antagonist binding site. Such antagonists have side-groups that project further out into the cleft formed between the two major lobes (S1 and S2) that comprise the glutamate binding domain of the NMDA receptor. Thus, we are targeting antagonists that are capable of interacting with the more variable regions of the receptor. The objectives of this project are to: 1) Synthesize and evaluate novel NMDA receptor antagonists that define the structural requirements for binding within the cleft domain of the different NR2 subunits. 2) Test our recently developed molecular models of NR2B and NR2C glutamate binding sites by making point mutations and one chimera that are predicted to have specific alterations in antagonist selectivity. 3) The results from novel antagonists (Aim 1) and point mutations (Aim 2) will be used to test, and if necessary, refine our molecular models of NR2B and NR2C glutamate binding sites. We will then construct NR2A and NR2D molecular models. We will then use the refined models, as well as the structure-activity information, to generate new subtype-selective cleft-binding antagonists. This process would include using automated, computer-assisted routines, as well as, visually-aided design. Given the high homology in secondary, but not primary, structure for the various glutamate receptors, we feel this unexplored approach to antagonist design has significant implications for developing subtype selective antagonists within each of the glutamate receptor families.

描述（改编自申请人摘要）： NMDA受体参与CNS的几种关键功能， 学习的细胞机制，疼痛感知，运动模式， 经验依赖性突触的形成等等。这些受体也是 参与癫痫，麻醉适应和神经元细胞死亡 缺血、头部和脊髓损伤以及HIV感染。目前，角色 不同的NMDA受体亚型在这些不同的行为中发挥作用， 未知我们建议开发亚型选择性拮抗剂，以促进 NMDA受体亚型在正常和异常CNS功能中的研究。 我们建议开发一类新的NMDA受体拮抗剂- "裂缝结合"拮抗剂。我们以前的拮抗剂开发研究， 以及我们的分子模型研究，使我们得出结论， 更高亚型选择性的拮抗剂需要大的侧基， 可以与位于初级结构外的独特氨基酸残基相互作用， 拮抗剂结合位点。这种拮抗剂具有侧基， 进入在两个主瓣（S1和S2）之间形成的裂缝中，所述两个主瓣包括 NMDA受体的谷氨酸结合域。因此， 拮抗剂，能够与更可变的区域相互作用， 受体。 本课题的主要目的是：1）合成和评价新型NMDA 受体拮抗剂，其定义了结合内的结构要求， 不同NR2亚基的裂缝结构域。2)测试我们最近开发的 NR2B和NR2C谷氨酸结合位点的分子模型 突变和一个嵌合体，预测有特定的改变， 拮抗剂选择性3)新拮抗剂（Aim 1）和点 突变（目标2）将用于测试，如果必要的话，完善我们的分子 NR2B和NR2C谷氨酸结合位点的模型。然后我们将构建NR2A 和NR 2D分子模型。然后，我们将使用改进的模型，以及 结构-活性信息，以产生新的亚型选择性断裂结合 对手。这一过程将包括使用自动化、计算机辅助 例程，以及视觉辅助设计。考虑到与DNA的高度同源性， 各种谷氨酸受体的二级结构，但不是一级结构，我们 我觉得这种未经探索的拮抗剂设计方法具有重要意义 用于开发每种谷氨酸内的亚型选择性拮抗剂， 受体家族