N-Methyl-D-aspartate receptors (NMDARs) are key regulators of synaptic plasticity in the central nervous system. Potentiation of NMDARs containing GluN2A subunit has been recently recognized as a promising therapeutic approach for neurological disorders. We identified a novel series of GluN2A positive allosteric modulator (PAM) with a pyridin-2-one scaffold. Initial lead compound 1 was discovered through in silico-based screening of virtual ligands with various monocyclic scaffolds. GluN2A PAM activity was increased by introduction of a methyl group at the 6-position of the pyridin-2-one ring and a cyano group in the side chain. Modification of the aromatic ring led to the identification of potent and brain-penetrant 6-methylpyridin-2-one 17 with a negligible binding activity for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Oral administration of 17 significantly enhanced rat hippocampal long-term potentiation (LTP). Thus, 17 would be a useful in vivo pharmacological tool to investigate complex NMDAR functions for the discovery of therapeutics toward diseases associated with NMDAR dysfunction

N -甲基-D-天冬氨酸受体 (NMDAR) 是中枢神经系统突触可塑性的关键调节因子。含有 GluN2A 亚基的 NMDARs 的增强最近被认为是一种有前途的神经系统疾病治疗方法。我们确定了一系列具有 pyridin-2-one 支架的新型 GluN2A 正变构调节剂 (PAM)。最初的先导化合物1是通过基于计算机的虚拟配体筛选与各种单环骨架发现的。GluN2A PAM 活性通过在 pyridin-2-one 环的 6 位引入甲基和在侧链引入氰基来增加。芳香环的修饰导致鉴定出有效的脑渗透剂 6-methylpyridin-2-one 17对 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) 的结合活性可忽略不计。口服17显着增强大鼠海马长时程增强 (LTP)。因此，17将是一种有用的体内药理学工具，用于研究复杂的 NMDAR 功能，以发现与 NMDAR 功能障碍相关的疾病的治疗方法