Significance of NMDA receptor-targeting compounds in neuropsychological disorders: An in-depth review

N-methyl-D-aspartate receptors (NMDARs), a subclass of glutamate-gated ion channels, play an integral role in the maintenance of synaptic plasticity and excitation-inhibition balance within the central nervous system (CNS). Any irregularities in NMDAR functions, whether hypo-activation or over-activation, can destabilize neural networks and impair CNS function. Several decades of experimental and clinical investigations have demonstrated that NMDAR dysfunction is implicated in the pathophysiology of various neurological disorders. Despite designing a long list of compounds that differentially modulate NMDARs, success in developing drugs that can selectively and effectively regulate various NMDAR subtypes while showing encouraging efficacy in clinical settings remains limited. A better understanding of the basic mechanism of NMDAR function, particularly its selective regulation in pathological conditions, could aid in designing effective drugs for the treatment of neurological conditions. Here, we reviewed the experimental and clinical investigations that studied the effects of available NMDAR modulators in various neurological disorders and weighed up the pros and cons of the use of these substances on the improvement of functional outcomes of these disorders. Despite numerous efforts to develop NMDAR modulatory drugs that did not produce the desired outcomes, NMDARs remain a significant target for advancing novel drugs to treat neurological disorders. This article reviews the complexity of NMDAR signaling dysfunction in different neurological diseases, the efforts taken to examine designed compounds targeting specific subtypes of NMDARs, including challenges associated with using these substances, and the potential enhancements in drug discovery for NMDAR modulatory compounds by innovative technologies.