含N -甲基- D -天冬氨酸受体GluN2B/C/D的选择性调节：靶向神经治疗的新前沿。

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-06-26 eCollection Date: 2025-07-10 DOI:10.1021/acsmedchemlett.5c00365

Yinlong Li, Steven H Liang

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引用次数: 0

摘要

n -甲基-d-天冬氨酸受体（NMDARs）是一类嗜离子性谷氨酸受体，介导整个中枢神经系统（CNS）的突触可塑性和兴奋性神经传递。NMDAR功能失调与自闭症、精神分裂症和抑郁症等多种神经系统疾病有关。因此，NMDAR被认为是关键的治疗靶点，广泛的研究集中在NMDAR调节剂的开发上。正变构调节剂（Positive allosteric modulators, pam）是一种很有前景的调节NMDARs功能减退的方法；然而，亚单位选择性pam的可用性仍然有限。最近的一项研究发现，通过结构-活性关系（SAR）优化，一系列GluN2B/C/ d偏序pam的效力提高了约20倍，亚基选择性高，为nmdars靶向药物开发提供了有价值的见解。

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Selective Modulation of the GluN2B/C/D Containing N‑Methyl‑d‑Aspartate Receptors: A New Frontier in Targeted Neurotherapeutics.

N-methyl-d-aspartate receptors (NMDARs) are a class of ionotropic glutamate receptors that mediate synaptic plasticity and excitatory neurotransmission throughout the central nervous system (CNS). Dysregulation of NMDAR function has been implicated in multiple neurological disorders such as autism, schizophrenia, and depression. Thus, NMDARs are considered crucial therapeutic targets, and extensive studies have focused on the development of NMDAR modulators. Positive allosteric modulators (PAMs) represent a promising approach to regulate NMDARs hypofunction; however, the availability of subunit-selective PAMs remains limited. A recent study has identified a series of GluN2B/C/D-biased PAMs with approximately 20-fold increased potency and high subunit selectivity through structure-activity relationship (SAR) optimization, which provides valuable insights for NMDARs-targeted drug development.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.