GNE 0723 is a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs, with an EC50 of 0.021μM and a maximal potentiation of 152%[1,2].
In vitro, Whole-cell recordings at room temperature (RT) from CHO cells expressing GluN2A-containing NMDARs showed that 1μM GNE 0723 enhanced the peak current and slowed the current deactivation in response to brief pulses of glutamate (Glu)[3].
In vivo, mouse clearance of GNE 0723 was 26mL·min–1·kg–1 and oral bioavailability was 24%[1]. GNE 0723 (3mg/kg; oral; every other day for 5 weeks) treatment improved memory retention in J20 mice and improved long-term memory consolidation in J20 and WT mice by the Morris water maze (MWM) test[3]. GNE 0723 (3mg/kg; oral; every other day for 5 weeks) enhances fear learning in Scn1a-KI mice[3].
References:
[1]. Villemure, Elisia, et al. "GluN2A-selective pyridopyrimidinone series of NMDAR positive allosteric modulators with an improved in vivo profile." ACS Medicinal Chemistry Letters 8.1 (2017): 84-89.
[2]. Li, Zhongtang, et al. "Discovery of novel and potent N-methyl-d-aspartate receptor positive allosteric modulators with antidepressant-like activity in rodent models." Journal of Medicinal Chemistry 64.9 (2021): 5551-5576.
[3]. Hanson, Jesse E., et al. "GluN2A NMDA receptor enhancement improves brain oscillations, synchrony, and cognitive functions in Dravet syndrome and Alzheimer’s disease models." Cell reports 30.2 (2020): 381-396.
GNE 0723是一种选择性作用于GluN2A亚基且能穿透血脑屏障的N-甲基-D-天冬氨酸受体（NMDAR）正向变构调节剂（PAM），其半数有效浓度（EC50）为0.021μM，最大增强作用为152%[1,2]。
在体外，室温下对表达含GluN2A的NMDAR的CHO细胞进行全细胞记录显示，1μM的 GNE 0723 能增强谷氨酸（Glu）短暂脉冲刺激下的峰值电流，并减缓电流失活速度[3]。
在体内，小鼠对GNE 0723的清除率为26mL·min–1·kg–1，口服生物利用度为24%[1]。通过莫里斯水迷宫（MWM）测试，GNE 0723（3mg/kg；口服；每隔一天给药一次，持续5周）治疗可改善J20小鼠的记忆保持能力，并提高J20和野生型小鼠的长期记忆能力[3]。GNE 0723（3mg/kg；口服；每隔一天给药一次，持续5周）能增强Scn1a-KI小鼠的恐惧学习能力[3]。