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

N-甲基-D-天冬氨酸受体（NMDAR）负责响应于谷氨酸和甘氨酸的共激动剂结合的兴奋性突触传递的缓慢组分。受体的结构观点是它们是由两个NR 1亚基和两个NR 2（A-D）亚基组成的异源四聚体受体。与每种特定NR 2亚基类型相关的差异表达模式为干预帕金森病、精神分裂症和缺血性细胞死亡等疾病提供了药理学依据。我们已经确定了几个不同类别的分子，是选择性的NR 2C/NR 2D受体亚型，通过中等通量的筛选奋进。初步数据表明，受体S2区内两种不同类型分子的重叠结合位点可能是用已发现的两种类型观察到的非竞争性、电压非依赖性拮抗作用的原因。为了验证这一假设，我们建议使用嵌合受体，计算机辅助建模，和合成化学，努力开发有效的和选择性的小分子，将允许描述的新的结合位点，以及药效团的小分子的描述。这些研究将提供一流的亚基选择性药理学工具，这将有助于我们进一步了解不同的NMDA受体所发挥的生理和病理生理作用。

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.