In this work, a novel structural series of brain-penetrant GluN2B NMDAR antagonists were designed, synthesized and biologically evaluated as anti-stroke therapeutic agents via merging the structures of NBP and known GluN2B ligands. Approximately half of them exhibited superior neuroprotective activity to NBP against NMDA-induced neurotoxicity in hippocampal neurons at 10 μM, and compound 45e and 45f exerted equipotent activity to ifenprodil, an approved GluN2B- selective NMDAR antagonist. In particular, 45e, with the most potent neuroprotective activity throughout this series, displayed dramatically enhanced activity (K<sub>i</sub> = 3.26 nM) compared to ifenprodil (K<sub>i</sub> = 14.80 nM) in Radioligand Competitive Binding Assay, and remarkable inhibition (IC<sub>50</sub> = 79.32 nM) against GluN1/GluN2B receptor-mediated current in Patch Clamp Assay. Meanwhile, 45e and its enantiomers exhibited low inhibition rate against the current mediated by other investigated receptors at the concentration of 10 μM, indicating their favorable selectivity for GluN1/GluN2B. In the rat model of middle cerebral artery ischemia (MCAO), 45e exerted comparable therapeutic efficacy to ifenprodil at the same dosage. In addition to the attractive in vitro and in vivo potency, 45e displayed a favorable bioavailability (F = 63.37%) and an excellent brain exposure. In further repeated dose toxicity experiments, compound 45e demonstrated an acceptable safety profile. With the above merits, 45e is worthy of further functional investigation as a novel anti-stroke therapeutic agent.