Discovery of novel positive allosteric modulators targeting GluN1/2A NMDARs as anti-stroke therapeutic agents.
RSC Med Chem
; 15(4): 1307-1319, 2024 Apr 24.
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| ID: mdl-38665828
ABSTRACT
Excitotoxicity due to excessive activation of NMDARs is one of the main mechanisms of neuronal death during ischemic stroke. Previous studies have suggested that activation of either synaptic or extrasynaptic GluN2B-containing NMDARs results in neuronal damage, whereas activation of GluN2A-containing NMDARs promotes neuronal survival against ischemic insults. This study applied a systematic in silico, in vitro, and in vivo approach to the discovery of novel and potential GluN1/2A NMDAR positive allosteric modulators (PAMs). Ten compounds were obtained and identified as potential GluN1/2A PAMs by structure-based virtual screening and calcium imaging. The neuroprotective activity of the candidate compounds was demonstrated in vitro. Subsequently, compound 15 (aegeline) was tested further in the model of transient middle cerebral artery occlusion (tMCAO) in vivo, which significantly decreased cerebral infarction. The mechanism by which aegeline exerts its effect on allosteric modulation was revealed using molecular dynamics simulations. Finally, we found that the neuroprotective effect of aegeline was significantly correlated with the enhanced phosphorylation of cAMP response element-binding protein (CREB). Our study discovered the neuroprotective effect of aegeline as a novel PAM targeting GluN1/2A NMDAR, which provides a potential opportunity for the development of therapeutic agents for ischemic stroke.
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2024
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