Cleft binding NMDA Receptor Subtype Antagonists

描述（由申请人提供）：NMDA受体在多种CMS功能中起关键作用，如学习、疼痛放大、运动模式产生和经验依赖性突触的形成和消除。这些受体还参与各种神经病理状况，如癫痫、阿片类药物成瘾、脑/脊髓损伤后的神经元细胞死亡、中风、艾滋病感染，并可能参与精神分裂症、阿尔茨海默氏症、帕金森病和亨廷顿氏症的病理生理学。然而，在缺乏选择性药理学工具的情况下，人们对不同的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种遗传上不同的NR2 NMDA受体亚基，但高选择性拮抗剂仅适用于NR2B亚基。在过去的几年里，我们已经产生了一系列新的化合物，这些化合物是已知的唯一的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，由于每个NR2亚基（以及各种AMPA和盐酸盐受体谷氨酸结合位点）的谷氨酸结合位点高度保守，开发高选择性药物已被证明是困难的。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，我们提出了两步方法来开发NR2D和NR2C亚型选择性拮抗剂。1)在非洲爪蟾卵母细胞中测试的重组受体，结合分子建模和定点诱变来确定一组NMDA拮抗剂的精确位置，这些NMDA拮抗剂足够大，可以到达谷氨酸结合袋边缘的亚基特异性氨基酸残基。2)利用这些结构信息，设计和测试预测与NR2D和其他NR2亚基特异性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，这些拮抗剂通过分子建模技术预测对含有NR2D亚基的NMDA受体具有高选择性。

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.