New advances in NMDA receptor pharmacology

N-Methyl-D-aspartate (NMDA) receptors are tetrameric ion channels containing two of four possible GluN2 sub-units. These receptors have been implicated for decades in neurological diseases such as stroke, traumatic brain injury, dementia and schizophrenia. The GluN2 sub-units substantially contribute to functional diversity of NMDA receptors and are distinctly expressed during development and among brain regions. Thus, subunit-selective antagonists and modulators that differentially target the GluN2 subunit might provide an opportunity to pharmacologically modify the function of select groups of neurons for therapeutic gain. A flurry of clinical, functional and chemical studies have together reinvigorated efforts to identify subunit-selective modulators of NMDA receptor function, resulting in a handful of new compounds that appear to act at novel sites. Here, we review the properties of new emerging classes of subunit-selective NMDA receptor modulators, which we predict will mark the beginning of a productive period of progress for NMDA receptor pharmacology.