State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Jiangsu Nhwa Pharmaceutical Co., Ltd. 69 Democratic South Road, Xuzhou, Jiangsu 221116, China.
J Med Chem. 2021 May 13;64(9):5551-5576. doi: 10.1021/acs.jmedchem.0c02018. Epub 2021 May 3.
-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na and Ca-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 caused a significant increase in NMDAR excitability and impressive activity in the forced swimming test. Moreover, compound 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.
