Cleft binding NMDA Receptor Subtype Antagonists

描述(由申请人提供)：NMDA受体关键参与CMS的各种功能，如学习、疼痛放大、运动模式生成以及经验依赖型突触的形成和消除。这些受体还参与各种神经病理情况，如癫痫、阿片成瘾、脑/脊髓损伤、中风、艾滋病感染后的神经细胞死亡，以及精神分裂症、阿尔茨海默病、帕金森病和亨廷顿病的病理生理学。然而，由于缺乏选择性的药理工具，对不同NMDA受体亚型在这些关键细胞过程和疾病状态中的作用知之甚少。虽然大部分功能和药理的异质性是由于四个遗传上不同的NR2 NMDA受体亚基，但高选择性的拮抗剂只对NR2B亚基可用。在过去的几年里，我们已经产生了一系列新的化合物，这些化合物是唯一已知的NR2C和NR2D药物，并已经揭示了NMDA受体亚型在突触生理和可塑性中的不同作用。然而，事实证明，开发高选择性试剂是困难的，因为中心谷氨酸结合位点对每个NR2亚基(以及各种AMPA和海人藻酸受体谷氨酸结合位点)都是高度保守的。我们现在已经确定了NR2谷氨酸结合位点的亚基特异性结构特征，并提出了开发NR2D和NR2C亚型选择性拮抗剂的两步法。1)使用分子模拟和在非洲爪哇卵母细胞上测试的重组受体的定点突变相结合的方法来定义精选的一组NMDA拮抗剂的精确放置，这些拮抗剂足够大，足以到达谷氨酸结合口袋边缘的亚单位特定氨基酸残基。2)利用这些结构信息，设计和测试预计与NR2D和其他NR2亚基特异的氨基酸残基相互作用的拮抗剂。使用这种方法，我们已经设计了几种通过分子建模技术预测对含有NR2D亚单位的NMDA受体具有高度选择性的拮抗剂。

DESCRIPTION (provided by applicant): NMDA receptors are critically involved in a variety of CMS functions such as learning, pain amplification, motor pattern generation, and experience-dependent synapse formation and elimination. These receptors are also involved in various neuropathological conditions such as epilepsy, opiate addiction, and neuronal cell death following head/spinal cord injury, sroke, AIDS infection, and possibly the pathophysiology in schizophrenia, Alzheimer's, Parkinson's, and Huntingon's. However, in the absence of selective pharmacological tools, relatively little is known about the role of different NMDA receptor subtypes in these critical cellular processes and disease states. While most of the functional and pharmacological heterogeneity is due to the four genetically-distinct NR2 NMDA receptor subunits, highly-selective antagonists are only available for the NR2B subuit. Over the past few years we have generated a novel series of compounds that are the only NR2C, and NR2D agents known and have already revealed differential roles for NMDA receptor subtypes in synaptic physiology and plasticity. However, it has proven difficult to develop highly-selective agents because the central glutamate binding site is highly conserved for each of the NR2 subunits (as well as for the various AMPA and kainate receptor glutamate binding sites). We have now identified the subunit-specific structural features of the NR2 glutamate binding sites and we propose a two-step approach to developing NR2D and NR2C subtype-selective antagonists. 1) Use a combination of molecular modeling and site-directed mutagenesis of recombinant receptors tested in Xenopus oocytes to define the precise placement of a select group of NMDA antagonists that are large enough to reach the subunit-specific amino acid residues at the edge of the glutamate-binding pocket. 2) Using this structural information, design and test antagonists that are predicted to interact with amino acid residues that are specific to NR2D and other NR2 subunits. Using this approach, we have already designed several antagonists that are predicted by molecular modeling techniques to be highly-selective for NR2D subunit-containing NMDA receptors.