Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience , University of Bristol , Bristol BS8 1TD , U.K.
School of Chemistry , National University of Ireland Galway , Galway H91TK33 , Ireland.
J Med Chem. 2019 Jan 10;62(1):3-23. doi: 10.1021/acs.jmedchem.7b01640. Epub 2018 Mar 5.
Excitatory activity in the CNS is predominately mediated by l-glutamate through several families of l-glutamate neurotransmitter receptors. Of these, the N-methyl-d-aspartate receptor (NMDAR) family has many critical roles in CNS function and in various neuropathological and psychiatric conditions. Until recently, the types of compounds available to regulate NMDAR function have been quite limited in terms of mechanism of action, subtype selectivity, and biological effect. However, several new classes of NMDAR agents have now been identified that are positive or negative allosteric modulators (PAMs and NAMs, respectively) with various patterns of NMDAR subtype selectivity. These new agents act at several newly recognized binding sites on the NMDAR complex and offer significantly greater pharmacological control over NMDAR activity than previously available agents. The purpose of this review is to summarize the structure-activity relationships for these new NMDAR modulator drug classes and to describe the current understanding of their mechanisms of action.
中枢神经系统中的兴奋活动主要通过几种 l-谷氨酸递质受体家族介导的 l-谷氨酸来实现。在这些受体中，N-甲基-d-天冬氨酸受体 (NMDAR) 家族在中枢神经系统功能和各种神经病理学和精神疾病状况中具有许多关键作用。直到最近，可用于调节 NMDAR 功能的化合物在作用机制、亚型选择性和生物学效应方面都非常有限。然而，现在已经确定了几类新型 NMDAR 药物，它们分别是正变构调节剂 (PAMs) 和负变构调节剂 (NAMs)，具有不同的 NMDAR 亚型选择性模式。这些新型药物作用于 NMDAR 复合物上的几个新识别结合位点，对 NMDAR 活性的药理学控制程度明显优于以前可用的药物。本文综述的目的是总结这些新型 NMDAR 调节剂类药物的构效关系，并描述目前对其作用机制的理解。
