CLEFT-BINDING NMDA RECEPTOR SUBTYPE ANTAGONISTS

裂口结合 NMDA 受体亚型拮抗剂

• 批准号: 6538985
• 负责人: DANIEL T MONAGHAN
• 金额: $ 27.92万
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6538985
• 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(改编自申请人的摘要)： NMDA受体参与中枢神经系统的几个关键功能，如 学习的细胞机制，痛觉，运动模式， 依赖经验的突触形成，以及其他。这些受体也是 参与癫痫、药物适应和随后的神经细胞死亡 脑缺血，头部和脊髓损伤，以及艾滋病毒感染。目前，这些角色 不同的NMDA受体亚型在这些不同的作用中起作用的是 未知。我们建议开发亚型选择性拮抗剂，以促进 中枢神经系统功能正常与异常的NMDA受体亚型研究 我们建议开发一种新的NMDA受体拮抗剂- “裂隙结合”的拮抗者。我们之前的对抗性发展研究，如 以及我们的分子模型研究，使我们得出这样的结论 亚型选择性更强的拮抗剂需要较大的侧基， 可以与位于初级生物外的独特的氨基酸残基相互作用 拮抗剂结合部位。这样的对手有侧基，这些侧基投射得更远 进入两个主叶(S1和S2)之间形成的裂缝，这两个裂缝包括 NMDA受体的谷氨酸结合区。因此，我们的目标是 能够与更多的可变区相互作用的拮抗剂 感受器。 本项目的目标是：1)合成和评价新型NMDA 定义结合的结构要求的受体拮抗剂 不同NR2亚基的裂解结构域。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 突变和一个嵌合体被预测具有特定的 拮抗剂选择性。3)新的拮抗剂的结果(目标1)和点 突变(目标2)将被用来测试，并在必要时提炼我们的分子 NR2B和NR2C谷氨酸结合位点模型。然后我们将建造NR2A 和NR2D分子模型。然后，我们将使用改进的模型以及 结构活性信息，生成新的亚型选择性裂解结合 对抗者。这一过程将包括使用自动化的、计算机辅助的 例行公事，以及视觉辅助设计。考虑到其中的高度同源性 各种谷氨酸受体的二级结构，但不是初级结构，我们 我觉得这种未被探索的对抗性设计方法具有重大意义 用于在每种谷氨酸中开发亚型选择性拮抗剂 受体家族。