Cleft binding NMDA Receptor Subtype Antagonists

描述（由申请人提供）：NMDA 受体关键参与多种 CMS 功能，例如学习、疼痛放大、运动模式生成以及经验依赖性突触形成和消除。这些受体还参与各种神经病理学病症，例如癫痫、阿片成瘾和头部/脊髓损伤后的神经元细胞死亡、中风、艾滋病感染，以及可能的精神分裂症、阿尔茨海默氏症、帕金森氏症和亨廷顿氏症的病理生理学。然而，由于缺乏选择性药理学工具，人们对不同 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。虽然大多数功能和药理学异质性是由于四个遗传上不同的 NR2 NMDA 受体亚基造成的，但高度选择性的拮抗剂仅适用于 NR2B 亚基。在过去的几年里，我们开发了一系列新型化合物，它们是唯一已知的 NR2C 和 NR2D 药物，并且已经揭示了 NMDA 受体亚型在突触生理学和可塑性中的不同作用。然而，事实证明开发高选择性试剂很困难，因为每个 NR2 亚基（以及各种 AMPA 和红藻氨酸受体谷氨酸结合位点）的中央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方法。 1) 结合分子建模和在非洲爪蟾卵母细胞中测试的重组受体的定点诱变来确定一组选定的 NMDA 拮抗剂的精确位置，这些拮抗剂的大小足以到达谷氨酸结合袋边缘的亚基特异性氨基酸残基。 2) 使用该结构信息，设计并测试预计与 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拮抗剂，通过分子建模技术预测这些拮抗剂对包含 NR2D 亚基的 NMDA 受体具有高度选择性。

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.