Identification of a novel class of allosteric modulators of the NMDA receptor

Abstract

Introduction: N-methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels that play key roles in processes underlying learning and memory. NMDA receptor dysfunction is thought to contribute to virtually every major neurological disorder, including Alzheimer's, Parkinson's, and Huntington's disease, stroke, epilepsy, neuropathic pain, schizophrenia, ADHD, chronic depression and ageing-related memory deficits. Despite the enormous potential of NMDA receptorbased therapeutics, drugs targeting this receptor have been mostly disappointing in clinical trials, due to a combination of intolerable side effects and poor efficacy. The aim of our present work is to develop a new class of NMDA receptor drugs for treating neurological disorders, which are expected to be efficacious, selective and safe. Methods: The approach is based on our recent observation suggesting that allosteric modulators bind to the heteromeric dimer interface formed by the NMDA receptor subunit NR1 and NR2 ligand binding domains. The 3D structures for 7,000 compounds from a virtual library were docked into the NR1-NR2A dimer interface and the binding affinity was estimated for each optimal pose, using the eHiTS software (www.simbiosys.com). The top-ranking compounds were characterized electro-physiologically using 2-electrode voltage clamp in Xenopus ooocytes. Results & Conclusion: Out of 10 top-ranking compounds tested, 3 were negative allosteric modulators, decreasing NMDA current by 17-25%. Six compounds enhanced NMDA receptor function by 17-73%, while 1 drug was ineffective. Our preliminary data suggest that this approach is feasible. Because only 0.1% of the available compounds have been screened in silico, we expect to identify a wide range of positive and negative allosteric modulators for the NMDA receptor.