Design and synthesis of novel GluN2A NMDAR positive allosteric modulators via scaffold hopping strategy as anti-stroke therapeutic agents.

[Display omitted] • Few positive allosteric modulators were reported in the NTD of GluN1/N2A NMDARs. • The scaffold hopping strategy was adopted to obtain new PAMs with stable molecular skeleton. • Candidate compound 5c selectively enhanced GluN1/N2A NMDARs function. • GluN1/N2A NMDARs positive allosteric modulators could be developed neuroprotective agents. NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. Activation of NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action, whereas over activating GluN2B-containing receptor results in excitotoxicity, increasing neuronal apoptosis. Our previous study has identified Npam 43 as a NMDAR positive allosteric modulators. However, the cis-trans isomerization impedes the development of Npam 43 as potential neuroprotective agents. To discover more potent and selective GluN2A NMDAR positive allosteric modulators, 38 derivatives were synthesized and evaluated their neuroprotective effect on glutamate-exposed PC-12 cells. The allosteric activities of compounds were evaluated using calcium imaging approaches. Among them, compound 5c exhibit GluN1/2A selectivity over GluN1/2B and show neuroprotective activity in vitro and in vivo. This study reported a series of GluN1/2A positive allosteric modulators as neuroprotective agents, and provided a potential opportunity to discover new drugs for stroke treatment. [ABSTRACT FROM AUTHOR]