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Abstract：
Neurodegenerative disorders (NDs) include a range of chronic conditions characterized by progressive neuronal loss, leading to cognitive, motor, and behavioral impairments. Common examples include Alzheimer\'s disease (AD) and Parkinson\'s disease (PD). The global prevalence of NDs is on the rise, imposing significant economic and social burdens. Despite extensive research, the mechanisms underlying NDs remain incompletely understood, hampering the development of effective treatments. Excitotoxicity, particularly glutamate-mediated excitotoxicity, is a key pathological process implicated in NDs. Targeting the N-methyl-D-aspartate (NMDA) receptor, which plays a central role in excitotoxicity, holds therapeutic promise. However, challenges, such as blood-brain barrier penetration and adverse effects, such as extrapyramidal effects, have hindered the success of many NMDA receptor antagonists in clinical trials. This review explores the molecular mechanisms of NMDA receptor antagonists, emphasizing their structure, function, types, challenges, and future prospects in treating NDs. Despite extensive research on competitive and noncompetitive NMDA receptor antagonists, the quest for effective treatments still faces significant hurdles. This is partly because the same NMDA receptor that necessitates blockage under pathological conditions is also responsible for the normal physiological function of NMDA receptors. Allosteric modulation of NMDA receptors presents a potential alternative, with the GluN2B subunit emerging as a particularly attractive target due to its enrichment in presynaptic and extrasynaptic NMDA receptors, which are major contributors to excitotoxic-induced neuronal cell death. Despite their low side-effect profiles, selective GluN2B antagonists like ifenprodil and radiprodil have encountered obstacles such as poor bioavailability in clinical trials. Moreover, the selectivity of these antagonists is often relative, as they have been shown to bind to other GluN2 subunits, albeit minimally. Recent advancements in developing phenanthroic and naphthoic acid derivatives offer promise for enhanced GluN2B, GluN2A or GluN2C/GluN2D selectivity and improved pharmacodynamic properties. Additional challenges in NMDA receptor antagonist development include conflicting preclinical and clinical results, as well as the complexity of neurodegenerative disorders and poorly defined NMDA receptor subtypes. Although multifunctional agents targeting multiple degenerative processes are also being explored, clinical data are limited. Designing and developing selective GluN2B antagonists/modulators with polycyclic moieties and multitarget properties would be significant in addressing neurodegenerative disorders. However, advancements in understanding NMDA receptor structure and function, coupled with collaborative efforts in drug design, are imperative for realizing the therapeutic potential of these NMDA receptor antagonists/modulators.
摘要：
神经退行性疾病（ND）包括一系列以进行性神经元丢失为特征的慢性疾病，导致认知，电机,和行为障碍。常见的例子包括阿尔茨海默病(AD)和帕金森病(PD)。NDS的全球患病率正在上升，造成重大的经济和社会负担。尽管进行了广泛的研究,NDS的潜在机制仍未完全理解，阻碍有效治疗方法的发展。兴奋毒性,特别是谷氨酸介导的兴奋性毒性，是与ND有关的关键病理过程。靶向N-甲基-D-天冬氨酸（NMDA）受体，在兴奋性毒性中起着核心作用，拥有治疗的希望。然而,挑战,如血脑屏障穿透和副作用，如锥体外系效应，阻碍了许多NMDA受体拮抗剂在临床试验中的成功。本文就NMDA受体拮抗剂的分子机制进行综述,强调他们的结构，函数,类型,挑战,以及治疗NDS的未来前景。尽管对竞争性和非竞争性NMDA受体拮抗剂进行了广泛的研究，寻求有效治疗仍然面临重大障碍。这部分是因为在病理条件下需要阻断的相同NMDA受体也负责NMDA受体的正常生理功能。NMDA受体的变构调制提出了一种潜在的替代方案，GluN2B亚基由于其在突触前和突触外NMDA受体中的富集而成为特别有吸引力的靶标，它们是兴奋性毒性诱导的神经元细胞死亡的主要贡献者。尽管它们的副作用很低，选择性GluN2B拮抗剂如艾芬普地尔和radiprodil在临床试验中遇到了诸如生物利用度差的障碍。此外，这些拮抗剂的选择性通常是相对的，因为它们已经被证明与其他GluN2亚基结合，尽管最低限度。在开发菲咯酸和萘甲酸衍生物方面的最新进展为增强的GluN2B提供了希望，GluN2A或GluN2C/GluN2D选择性和改善的药效学性质。NMDA受体拮抗剂开发的其他挑战包括相互矛盾的临床前和临床结果。以及神经退行性疾病的复杂性和定义不清的NMDA受体亚型。尽管针对多个变性过程的多功能药物也在探索中，临床数据有限。设计和开发具有多环部分和多靶标性质的选择性GluN2B拮抗剂/调节剂在解决神经退行性疾病方面将是重要的。然而,理解NMDA受体结构和功能的进展，加上药物设计方面的合作努力，对于实现这些NMDA受体拮抗剂/调节剂的治疗潜力是必要的。
