期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 9, 页码 5551-5576出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c02018
关键词
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资金
- National Major Scientific and Technological Special Project for Significant New Drugs Development [2018ZX09711002-013-004, 2018ZX09735-001]
- National Natural Science Foundation of China (NSFC) [81872730]
A series of furan-2-carboxamide analogues were identified as novel NMDAR-positive allosteric modulators, with FS2921 showing potential antidepressant effects. Compound 32h exhibited increased NMDAR excitability in vitro and significant antidepressant activity, with a favorable PK/PD profile. This study presents a new potential opportunity for discovering new antidepressants through novel NMDAR PAMs.
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.
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