アブカムでは最適な動作のために Google Chrome など最新ブラウザでの閲覧を推奨します。
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.
1. Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B. & Seeburg, P. H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529-540 (1994).
2. Buller, A. L. & Monaghan, D. T. Pharmacological heterogeneity of NMDA receptors: characterization of NR1a/NR2D heteromers expressed in Xenopus oocytes. Eur J Pharmacol 320, 87–94 (1997).
3. Collingridge, G. L. et al. The NMDA receptor as a target for cognitive enhancement. Neuropharmacology 64, 13–26 (2013).
4. Davies, J., Francis, A. A., Jones, A. W. & Watkins, J. C. 2-Amino-5-phosphonovalerate (2APV), a potent and selective antagonist of amino acid-induced and synaptic excitation. Neurosci Lett 21, 77–81 (1981).
5. Davies, J. & Watkins, J. C. Actions of D and L forms of 2-amino-5-phosphonovalerate and 2-amino-4-phosphonobutyrate in the cat spinal cord. Brain Res 235, 378–386 (1982).
6. Collingridge, G. L., Kehl, S. J. & McLennan, H. Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J Physiol (Lond) 334, 33–46 (1983).
7. Dudek, S. M. & Bear, M. F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc Natl Acad Sci USA 89, 4363–4367 (1992).
8. Morris, R. G., Anderson, E., Lynch, G. S. & Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319, 774–776 (1986).
9. Lodge, D. The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature. Neuropharmacology 56, 6–21 (2009).
10. Anis, N. A., Berry, S. C., Burton, N. R. & Lodge, D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol 79, 565–575 (1983).1. Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B. & Seeburg, P. H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529–540 (1994).
11. Evans, R. H., Francis, A. A. & Watkins, J. C. Selective antagonism by Mg2+ of amino acid-induced depolarization of spinal neurones. Experientia 33, 489–491 (1977).
12. Lodge, D. & Mercier, M. S. Ketamine and phencyclidine: the good, the bad and the unexpected. Br J Pharmacol 172, 4254–4276 (2015).
13. Morris, H. & Wallach, J. From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Test. Analysis 6, 614–632 (2014).
14. Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47, 351–354 (2000).
15. Zarate, C. A. et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856–864 (2006).
16. Iadarola, N. D. et al. Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Ther Adv Chronic Dis 6, 97–114 (2015).
17. Caddy, C. et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev 9, CD011612 (2015).
18. McCloud, T. L. et al. Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults. Cochrane Database Syst Rev 9, CD011611 (2015).
19. Preskorn, S. H. et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 28, 631–637 (2008).
20. Ibrahim, L. et al. A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J Clin Psychopharmacol 32, 551–557 (2012).
21. Newport, D. J. et al. Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. Am J Psychiatry 172, 950–966 (2015).
22. Monaghan, D. T., Irvine, M. W., Costa, B. M., Fang, G. & Jane, D. E. Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators. NEUROCHEMISTRY INTERNATIONAL 61, 581–592 (2012).1. Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B. & Seeburg, P. H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529–540 (1994).