Rationally Designing Subunit Selective Antagonists for NR2C/D containing NMDA rec

描述(由申请人提供)： N-甲基-D-天冬氨酸受体(NMDAR)负责兴奋性突触传递的慢成分，以响应谷氨酸和甘氨酸的共同激动剂结合。受体的结构观点认为它们是由两个NR1亚基和两个NR2(A-D)亚基组成的异四聚体受体。与每个特定NR2亚单位类型相关的差异表达模式为干预帕金森氏症、精神分裂症和缺血性细胞死亡等疾病提供了药理学基础。通过中等通量筛选，我们已经确定了几种不同类别的分子，它们对NR2C/NR2D受体亚型具有选择性。初步数据表明，在受体的S2区域内，两类不同分子的重叠结合部位可能是已发现的两类分子观察到的非竞争性、电压无关拮抗作用的原因。为了验证这一假说，我们建议使用嵌合受体、计算机辅助建模和合成化学来努力开发有效和选择性的小分子，这些小分子将允许描述新的结合位点，以及对小分子的药效团描述。这些研究将提供一流的亚基选择性药理学工具，有助于我们进一步了解不同NMDA受体所发挥的生理和病理生理作用。) 公共卫生相关性： 该项目旨在开发小分子，使我们能够开始了解特定的NMDA受体亚型在疾病状态中的作用。受体由两个NR1亚基和两个NR2(A-D)亚基组成。含有NMDA的大脑中不同受体组合的表达模式为干预帕金森氏症、精神分裂症和阿尔茨海默氏症等疾病提供了药理学基础。)

DESCRIPTION (provided by applicant): N-methyl-D-aspartate receptors (NMDARs) are responsible for the slow component of excitatory synaptic transmission in response to co-agonist binding of glutamate and glycine. The structural view of the receptors is that they are hetero-tetrameric receptors composed of two NR1 subunits and two NR2(A-D) subunits. The differential expression patterns associated with each particular NR2 subunit type present pharmacological rationale for intervention in diseases such as Parkinson's, schizophrenia, and ischemic cell death. We have identified several distinct classes of molecules that are selective against the NR2C/NR2D receptor subtypes through a medium-throughput screening endeavor. Preliminary data suggest an overlapping binding site for two distinct classes of molecules within the S2 region of the receptor may be responsible for the non- competitive, voltage independent antagonism observed with two of the classes that have been discovered. In order to test this hypothesis, we are proposing to use chimeric receptors, computer assisted modeling, and synthetic chemistry in an effort to develop potent and selective small molecules that will allow for description of the novel binding site, as well as a pharmacophore description of the small molecules. These studies will provide first in class subunit-selective pharmacological tools that will aid in furthering our understanding of the physiological and patho-physiological roles played by different NMDA receptors.) PUBLIC HEALTH RELEVANCE: This project aims to develop small molecules that will allow us to begin to understand the role of particular NMDA receptor subtypes in disease states. The receptors are composed of two NR1 subunits and two NR2(A- D) subunits. The expression patterns of the different receptor combinations within the brain containing NMDA present pharmacological rationale for intervention in diseases such as Parkinson's, schizophrenia, and Alzheimer's. )