Development of GluN2A NMDA receptor positive allosteric modulators: Recent advances and perspectives

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-04-10 DOI:10.1016/j.bmc.2025.118194

Ping Li , Jiacheng Wang , Mengjiao Wang , Xin Chen , Hongyu Zhu , Mingxin Dong

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Abstract

N-methyl-d-aspartate (NMDA) receptors, functioning as glutamate-gated ion channels, mediate the permeation of Ca²⁺ and are essential for excitatory synaptic transmission and synaptic plasticity within the central nervous system (CNS). During brain development, there is a switch from an early dominance of GluN2B subunit expression to the incorporation of GluN2A subunits at mature synapses. NMDARs hypofunction is implicated in various psychiatric disorders, and activation of NMDARs containing GluN2A has recently attracted attention as a promising therapeutic approach for treating these diseases. This review focuses on the selective positive allosteric modulators (PAMs) that specifically target the ligand-binding domain (LBD) and N-terminal domain (NTD) regions of GluN2A subtype, as well as non-subunit selective PAMs, and discusses their implications in neuropsychiatric diseases such as stroke, depression, Alzheimer’s disease, and Huntington’s disease.

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GluN2A NMDA受体阳性变构调节剂的研究进展及展望

n -甲基-d-天冬氨酸（NMDA）受体作为谷氨酸门控离子通道，介导Ca2+的渗透，是中枢神经系统（CNS）兴奋性突触传递和突触可塑性所必需的。在大脑发育过程中，从早期GluN2B亚基表达的优势转变为成熟突触中GluN2A亚基的结合。NMDARs功能障碍与多种精神疾病有关，而激活含有GluN2A的NMDARs作为治疗这些疾病的一种有希望的治疗方法最近引起了人们的关注。本文综述了GluN2A亚型特异性靶向配体结合域（LBD）和n端结构域（NTD）区域的选择性阳性变构调节剂（PAMs），以及非亚基选择性PAMs，并讨论了它们在脑卒中、抑郁症、阿尔茨海默病和亨廷顿病等神经精神疾病中的意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.