Discovery of Dihydropyrrolo[1,2‑a]pyrazin-3(4H)‑one-Based Second-Generation GluN2C- and GluN2D-Selective Positive Allosteric Modulators (PAMs) of the N‑Methyl‑d‑Aspartate (NMDA) Receptor

The N-methyl-d-aspartate receptor (NMDAR) is an ion channel that mediates the slow, Ca2+-permeable component of glutamatergic synaptic transmission in the central nervous system (CNS). NMDARs are known to play a significant role in basic neurological functions, and their dysfunction has been implicated in several CNS disorders. Herein, we report the discovery of second-generation GluN2C/D-selective NMDAR-positive allosteric modulators (PAMs) with a dihydropyrrolo­[1,2-a]­pyrazin-3­(4H)-one core. The prototype, R-(+)-EU-1180-453, exhibits log unit improvements in the concentration needed to double receptor response, lipophilic efficiency, and aqueous solubility, and lowers cLogP by one log unit compared to the first-generation prototype CIQ. Additionally, R-(+)-EU-1180-453 was found to increase glutamate potency 2-fold, increase the response to maximally effective concentration of agonist 4-fold, and the racemate is brain-penetrant. These compounds are useful second-generation in vitro tools and a promising step toward in vivo tools for the study of positive modulation of GluN2C- and GluN2D-containing NMDA receptors.

N-甲基-D-天冬氨酸受体（N-methyl-d-aspartate receptor, NMDAR）是一类介导中枢神经系统（CNS）内谷氨酸能突触传递的缓慢钙通透组分的离子通道。已知NMDAR在基础神经功能中发挥关键作用，其功能异常与多种中枢神经系统疾病密切相关。本文报道了一类以二氢吡咯并[1,2-a]吡嗪-3(4H)-酮为母核的第二代GluN2C/D选择性NMDAR正变构调节剂（positive allosteric modulators, PAMs）。原型化合物R-(+)-EU-1180-453在使受体响应翻倍所需浓度、亲脂效率与水溶性方面均实现了对数单位级提升，且相较于第一代原型化合物CIQ，其计算脂水分配系数（cLogP）降低了一个对数单位。此外，研究发现R-(+)-EU-1180-453可使谷氨酸效价提升2倍，对激动剂最大有效浓度的响应提升4倍，且其外消旋体具备血脑屏障穿透性。此类化合物是极具应用价值的第二代体外研究工具，同时为靶向含GluN2C与GluN2D亚基的NMDA受体正变构调节研究的体内工具开发迈出了富有前景的一步。