Discovery of Novel and Potent N-Methyl-D-aspartate Receptor Positive Allosteric Modulators with Antidepressant-like Activity in Rodent Models

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.

Automated summary

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.