Selective Modulation of the GluN2B/C/D Containing N‑Methyl‑d‑Aspartate Receptors: A New Frontier in Targeted...

N-methyl-d-aspartate receptors (NMDARs) are a class of ionotropic glutamate receptors that mediate synaptic plasticity and excitatory neurotransmission throughout the central nervous system (CNS). Dysregulation of NMDAR function has been implicated in multiple neurological disorders such as autism, schizophrenia, and depression. Thus, NMDARs are considered crucial therapeutic targets, and extensive studies have focused on the development of NMDAR modulators. Positive allosteric modulators (PAMs) represent a promising approach to regulate NMDARs hypofunction; however, the availability of subunit-selective PAMs remains limited. A recent study has identified a series of GluN2B/C/D-biased PAMs with approximately 20-fold increased potency and high subunit selectivity through structure-activity relationship (SAR) optimization, which provides valuable insights for NMDARs-targeted drug development.