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

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.

Context is key: glucocorticoid receptor and corticosteroid therapeutics in outcomes after traumatic brain injury

“…For example, previous work has linked GR to N-methyl-D-aspartate receptor (NMDAR) activity in the hippocampus, which is known to contribute to TBI-induced excitotoxicity and cognitive deficits (Zhang et al, 2012 ; Baracaldo-Santamaría et al, 2022 ). NMDAR agonists have shown promise in improving cognition after TBI, but extensive issues regarding their safety and efficacy have limited their therapeutic potential and stalled clinical studies (Khormali et al, 2022 ; Hanson et al, 2024 ). A closer look at the role of GR in activity of NMDAR and other surface receptors may shed light on previously unexplored mechanisms of excitotoxicity after TBI.…”

Glutamate and excitotoxicity in central nervous system disorders: ionotropic glutamate receptors as a target for neuroprotection

“…The equilibrium kept by these transporters, supporting a significant gradient of glutamate across cell membranes, theoretically maintains low extracellular glutamate concentrations. However, studies using NMDA receptors as probes suggest that resting extracellular glutamate concentrations might be higher, 35 raising intriguing questions about the dynamic interplay of transporters in different synaptic conditions.…”

“…However, the design and implementation of combination therapy regimens necessitate careful consideration of factors such as drug interactions, dosing schedules, and safety profiles to optimize therapeutic outcomes while minimizing the risk of adverse events. 35 iGluRs are emerging as promising targets for therapeutic interventions tailored to specific cell types within the nervous system. 77 There's a growing focus on the role of iGluRs in cell-targeted therapy.…”

GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases

“…These studies have deepened our understanding of how dysfunction in NMDA receptors contributes to neurological disorders. Notably, NMDA receptor hypofunction has been implicated in schizophrenia, and some studies have explored NMDA receptor-based treatments for the condition [88]. 4.…”