1. Discovery of Novel and Potent N-Methyl-<scp>d</scp>-aspartate Receptor Positive Allosteric Modulators with Antidepressant-like Activity in Rodent Models
- Author
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Fan Fang, Zhenming Liu, Guanxing Cai, Liangren Zhang, Xiangqing Xu, Zhongjun Li, Minghua Fan, Wenchao Li, Yiyan Li, Zhuo Huang, Zhongtang Li, Guisen Zhang, Yinli Qiu, Yuxi Wang, Xuehui Lv, Jingjing Lian, and Ruqiu Zheng
- Subjects
biology ,Chemistry ,hERG ,Allosteric regulation ,Long-term potentiation ,Pharmacology ,nervous system ,mental disorders ,Drug Discovery ,Synaptic plasticity ,biology.protein ,Molecular Medicine ,NMDA receptor ,Antidepressant ,Receptor ,Behavioural despair test - Abstract
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.
- Published
- 2021
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