NMDA Receptor Antagonists as Antidepressant and Antidementia Drugs: Recent Developments and Future Prospects

N-Methyl-D-aspartate (NMDA) receptor (NR) antagonists have contributed to the major advances in research of excitatory synaptic transmission, neuronal excitotoxicity, and neurodegenerative disorders. Activation of the NRs evokes a rapid Ca2+ influx into neurons, resulting in an activation of a variety of intracellular signal cascades, Ca2+ mobilization, and alterations in membrane channel activity and gene expression. The signal transduction mechanisms play a fundamental role in how the brain functions physiologically but are also at the core of neural injury and dysfunction. Evidence is emerging that abnormal NR activation underlies the development of depressive symptoms and of many forms of dementia. Correcting abnormal activity of the NRs thus represents an attractive and essential therapeutic strategy in antidepressant and antidementia medications. NR antagonism can be achieved pharmacologically through blocking the NR / complex at its various binding sites, including the NR glutamate-binding site, the ion channel binding site, the glycine co-agonist site, the polyamine binding site, and the redox modulatory site(s). Agents that have antagonistic activity at the different sites show differential structure-activity relationships, possess distinct pharmacological profiles, and therefore have different therapeutic potentials. This review summarizes current knowledge and developments concerning a variety of NR antagonists and discusses their potential as pharmacological drugs in the treatments of depression and dementia.