N-Methyl-d-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family and play a crucial role in learning and memory by regulating synaptic plasticity. Activation of NMDARs containing GluN2A, one of the NMDAR subunits, has recently attracted attention as a promising therapeutic approach for neuropsychiatric diseases such as schizophrenia, depression, and epilepsy. In the present study, we developed potent and brain-penetrable GluN2A-selective positive allosteric modulators. Lead compound 2b was generated by scaffold hopping of hit compound 1, identified from the internal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-focused compound library through a high-throughput screening campaign. Subsequent optimization of the lead compound, including a structure-based drug design approach, resulted in the identification of a potent GluN2A PAM (R)-9, which possessed high selectivity against both subtypes of AMPAR and NMDAR. Furthermore, (R)-9 significantly enhanced long-term potentiation in the rat hippocampus 24 h after oral administration, indicating that this molecule is a potentially useful in vivo pharmacological tool for treating psychiatric diseases.

N-甲基-d-天冬氨酸受体（ NMDARs）是离子型谷氨酸受体家族的成员，通过调节突触可塑性在学习和记忆中发挥关键作用。含有 GluN2A（NMDAR 亚基之一）的 NMDAR 的激活最近作为一种有前途的神经精神疾病（如精神分裂症、抑郁症和癫痫）的治疗方法引起了人们的关注。在本研究中，我们开发了有效且可穿透大脑的 GluN2A 选择性正变构调节剂。先导化合物2b由命中化合物1的支架跳跃产生，通过高通量筛选活动从内部以 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体 (AMPAR) 为重点的化合物库中鉴定。先导化合物的后续优化，包括基于结构的药物设计方法，导致鉴定出一种有效的 GluN2A PAM ( R )-9，它对 AMPAR 和 NMDAR 的两种亚型都具有高选择性。此外，( R )-9在口服给药后 24 小时显着增强了大鼠海马的长期增强作用，表明该分子是一种潜在的用于治疗精神疾病的体内药理学工具。