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NMDARs of different subunit composition are expressed in different regions of the brain, with their expression changing during development, permitting in principle selective pharmacological targeting of different receptor populations1,2. Thus, NMDARs are interesting as targets for pharmacological intervention and cognitive enhancement3. Concurrently with the development of the NMDA receptor selective competitive antagonists4,5, which helped to establish their pivotal role in synaptic plasticity6,7 and learning and memory8, a number of non-competitive NMDAR receptor ligands were characterized also9. These included dissociative anesthetics phencyclidine (PCP) and ketamine10, which were found to block the NMDA receptor channel-pore, similarly to Mg2+11. PCP provided good analgesia in man, however signs of delirium and psychosis were, following recovery, reminding of symptoms of schizophrenia and laying basis for the glutamate hypothesis of the disease12. This sparkled an interest in glutamate receptors as targets for antipsychotic medication9,12 and was accompanied by non-medical use of the dissociative drugs13.
Ketamine, being ~ 10 times less potent than PCP at the NMDA receptor, showed fewer side effects and found its clinical use as a drug for analgesia and anesthesia9,10,12. Notably, another NMDA receptor channel blocker memantine is in use for treatment of Alzheimer’s disease whereas MK-801 is particularly popular amongst scientists as a research tool due to its features that include high potency and use-dependency12. Ketamine and memantine remain the only two drugs targeting the NMDA receptor, which have made it into the clinic, although their use is quite dissimilar.
Interest in the NMDA receptor channel blockers and other glutamate receptor ligands was rekindled more recently by the discovery that ketamine is effective as a treatment for depression, which is otherwise treatment resistant14-16. Although there is little doubt today that ketamine can provide a rapid anti-depressive response it is not clear why other NMDAR channel blockers do not produce similar effects17,18. It has been suggested that the explanation might be in the differential affinity of the uncompetitive NMDA receptor ligands at NMDARs composed of different subunits in combination with specific pharmacodynamics and pharmacokinetics that make ketamine especially suited for treatment of depression12. Although further work is needed to resolve this issue, GluN2B subunit-containing NMDARs have been implicated in the ketamine mediated antidepressant effects and negative allosteric modulators targeting this subunit have shown promise in the clinical trials19-21. Thus, with progress in development of subunit selective positive and negative allosteric modulators of NMDA receptors, improved targeting of NMDARs for treatment of depression and various other neuropathological and psychiatric conditions might just become possible3,22.
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