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Both N-methyl-D-aspartate (NMDA) receptor, one of the subtypes of ionotropic glutamatergic receptors at the vast majority of excitatory synapses, and the type A γ-aminobutyric acid receptor (GABAAR), the principal ionotropic GABARs at the inhibitory GABAergic synapses play essential roles in regulating neuronal activities in the mammalian central nervous system (CNS). Their dysfunctions contribute to the pathogenesis of many neurological disorders. Overactivation of NMDAR-mediated excitotoxicity is a common cause of many neurodegenerative diseases including stroke. There are two prevalent theories, the ‘NMDAR subtype hypothesis’ that proposes that activating GluN2A-containing NMDAR promotes neuronal survival, whereas activating GluN2B-containing NMDARs leads to neuronal death, and the ‘NMDAR location hypothesis’ that suggests that activating synaptic, primarily GluN2A-containing NMDARs favors neuronal survival while activating extrasynaptic, predominantly GluN2B-containing NMDARs induces neuronal death. Since both hypotheses support allosteric modulators that potentiate GluN2A function and inhibit GluN2B function may have promising potentials as a new and more effective class of neuroprotective therapy for stroke, we performed computer-aided virtual screening and in-silico drug design to discover a lead compound 813 that functions as an NMDAR dual allosteric modulator (Ndam) that potentiates GluN1/GluN2A and at the same time inhibits GluN1/GluN2B. We further optimized Ndam813 and thereby developed two more efficacious compounds, Ndam830 and Ndam844. Ndam830 protected cortical neurons …