374909-94-1Relevant articles and documents
Discovery of Novel and Potent N-Methyl- d -aspartate Receptor Positive Allosteric Modulators with Antidepressant-like Activity in Rodent Models
Li, Zhongtang,Cai, Guanxing,Fang, Fan,Li, Wenchao,Fan, Minghua,Lian, Jingjing,Qiu, Yinli,Xu, Xiangqing,Lv, Xuehui,Li, Yiyan,Zheng, Ruqiu,Wang, Yuxi,Li, Zhongjun,Zhang, Guisen,Liu, Zhenming,Huang, Zhuo,Zhang, Liangren
, p. 5551 - 5576 (2021/05/31)
N-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na+ and Ca2+-permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure-activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound 32h caused a significant increase in NMDAR excitability in vitro and impressive activity in the forced swimming test. Moreover, compound 32h showed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.
