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Tailoring allosteric modulators of NMDA receptors and GABA-A receptors for neurological disorders Chen, Wenlin


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 from NMDA-induced excitotoxicity and H2O2-induced oxidative stress, and also reduced ischemia-induced infarct volume, and promoted behavioral recoveries in rat MCAo models. Thus, our results strongly suggest that Ndam830 by promoting synaptic/GluN2A-containing NMDAR mediated cell survival signaling and inhibiting extrasynaptic/GluN2B-containing receptor mediated cell death signaling, is a novel neuroprotective stroke therapeutic. Ndam844 is a potent pan-NMDAR potentiator that can potentially treat NMDAR hypofunction related disorders. Apart from NMDARs, dysfunction of GABAARs is also implicated in various neurological conditions. Using electrophysiological and biochemical methods, we characterized the functional alterations of two de novo GABAAR variants T292S and T292I identified in patients with epileptic encephalopathy (EE) and developmental delay. Moreover, we found clinically approved allosteric modulators of GABAAR that may treat the patients carrying the variants. In summary, allosteric modulators of both NMDARs and GABAAR showed great therapeutic potential for neurological disorders.

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