Therapeutic potential of N-methyl-D-aspartate receptor modulators in psychiatry

• Authors: Jesse E. Hanson, Genentech Inc.; Hongjie Yuan, Emory University; Riley E. Perszyk, Emory University; Tue G. Banke, Emory University; Hao Xing, Emory University; Ming-Chi Tsai, Genentech Inc.; Frank S. Menniti, University of Rhode Island, Kingston; Stephen Traynelis, Emory University
• Journal Title: Neuropsychopharmacology
• Volume: Volume 49, Number 1
• Publisher: Springer Nature | 2023-06-27, Pages 51-66
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41386-023-01614-3
• Subjects: Biology, Neuroscience; Health Sciences, Pharmacology; Health Sciences, General
• Keywords: Pharmacology; Ion channels in the nervous system

Abstract

N-methyl-D-aspartate (NMDA) receptors mediate a slow component of excitatory synaptic transmission, are widely distributed throughout the central nervous system, and regulate synaptic plasticity. NMDA receptor modulators have long been considered as potential treatments for psychiatric disorders including depression and schizophrenia, neurodevelopmental disorders such as Rett Syndrome, and neurodegenerative conditions such as Alzheimer’s disease. New interest in NMDA receptors as therapeutic targets has been spurred by the findings that certain inhibitors of NMDA receptors produce surprisingly rapid and robust antidepressant activity by a novel mechanism, the induction of changes in the brain that well outlast the presence of drug in the body. These findings are driving research into an entirely new paradigm for using NMDA receptor antagonists in a host of related conditions. At the same time positive allosteric modulators of NMDA receptors are being pursued for enhancing synaptic function in diseases that feature NMDA receptor hypofunction. While there is great promise, developing the therapeutic potential of NMDA receptor modulators must also navigate the potential significant risks posed by the use of such agents. We review here the emerging pharmacology of agents that target different NMDA receptor subtypes, offering new avenues for capturing the therapeutic potential of targeting this important receptor class.