Li Yinlong, Liang Steven H
Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States.
ACS Med Chem Lett. 2025 Jun 26;16(7):1226-1230. doi: 10.1021/acsmedchemlett.5c00365. eCollection 2025 Jul 10.
-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.
N-甲基-D-天冬氨酸受体（NMDARs）是一类离子型谷氨酸受体，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功能失调与多种神经系统疾病有关，如自闭症、精神分裂症和抑郁症。因此，NMDARs被认为是关键的治疗靶点，大量研究集中在NMDAR调节剂的开发上。正变构调节剂（PAMs）是调节NMDAR功能低下的一种有前景的方法；然而，亚基选择性PAMs的可用性仍然有限。最近一项研究通过构效关系（SAR）优化，鉴定出一系列对GluN2B/C/D有偏向性的PAMs，其效力提高了约20倍，且具有高亚基选择性，这为以NMDARs为靶点的药物开发提供了有价值的见解。
