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Chemical Compound Review

NMDA     (2R)-2-methylaminobutanedioic acid

Synonyms: N-Me-D-Asp-OH, n-methyl-<scp, Lopac-M-3262, Tocris-0114, CHEMBL291278, ...
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Disease relevance of NMDA

  • Protein-tyrosine phosphorylation is a new mechanism for regulating NMDA receptors and may be important in neuronal development, plasticity and toxicity [1].
  • Besides glucocorticoids, excitatory amino acids and N-methyl-D-aspartate (NMDA) receptors are involved in these two forms of plasticity as well as in neuronal death that is caused in pyramidal neurons by seizures and by ischemia [2].
  • The modulation of GABAergic inhibition by NMDA receptors may cause the synaptic plasticity which underlies the kindling model of epilepsy [3].
  • When we targeted the N-methyl-D-aspartic acid (NMDA) excitatory amino acid receptor with an AAV-delivered antisense oligonucleotide, however, the promoter determined whether focal seizure sensitivity was significantly attenuated or facilitated [4].
  • Serum withdrawal induced a three- to fourfold increase in cell death of NG108 neuroblastoma cells, and this apoptosis was largely blocked by increasing the intracellular Ca2+ concentration with NMDA (N-methyl-D-aspartate) or KCl or by transfection with constitutively active CaM-KK [5].
  • Neu2000 may be a novel therapy for combating both NMDA receptor-mediated excitotoxicity and oxidative stress, the two major routes of neuronal death in ischemia, offering profound neuroprotection and an extended therapeutic window [6].

Psychiatry related information on NMDA


High impact information on NMDA

  • Antagonists of N-methyl-D-aspartate (NMDA) channels or voltage-gated Na(+) or certain types of Ca(2+) channels can postpone or mitigate SD or HSD, but it takes a combination of drugs blocking all known major inward currents to effectively prevent HSD [12].
  • Furthermore, calmodulin binding to NR1 causes a 4-fold reduction in NMDA channel open probability [13].
  • We applied the gene targeting to the NMDAR1 gene and created a mutant mouse that lacks functional NMDA receptors [14].
  • NMDA (N-methyl-d-aspartate) receptors (NMDARs) are a principal subtype of excitatory ligand-gated ion channel with prominent roles in physiological and disease processes in the central nervous system [15].
  • D-serine synthesis and release by astrocytes as an endogenous ligand for the "glycine" site of N-methyl D-aspartate (NMDA) receptors defy the concept that a neurotransmitter must be synthesized by neurons [16].

Chemical compound and disease context of NMDA


Biological context of NMDA

  • Drugs that antagonize N-methyl-D-aspartate (NMDA)-receptor activity, which is required for long-term potentiation (LTP) at various hippocampal synapses, block LTP and impair watermaze learning [23].
  • This is due to the action of glycine at a novel strychnine-resistant binding site with an anatomical distribution identical to that for NMDA receptors, suggesting that the NMDA receptor channel complex contains at least two classes of amino-acid recognition site [24].
  • The contribution of AMPA and NMDA receptors to synaptic transmission and plasticity is well established [25].
  • Although phosphorylation and dephosphorylation of glutamate receptors may participate in several lasting physiological and pathological alterations of neuronal excitability, the physiological control of this cycle for NMDA channels has not yet been established [26].
  • Neurotransmission at most excitatory synapses in the brain operates through two types of glutamate receptor termed alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors; these mediate the fast and slow components of excitatory postsynaptic potentials respectively [27].

Anatomical context of NMDA


Associations of NMDA with other chemical compounds


Gene context of NMDA

  • The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) serves critical functions in physiological and pathological processes in the central nervous system, including neuronal development, plasticity and neurodegeneration [30].
  • Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A [41].
  • By co-immunoprecipitation with subunit-specific antibodies, we present here direct evidence that NMDA receptors exist in rat neocortex as heteromeric complexes of considerable heterogeneity, some containing both NR2A and NR2B subunits [42].
  • Genetic knockout of NR3A in mice results in enhanced NMDA responses and increased dendritic spines in early postnatal cerebrocortical neurons [41].
  • Upon expression in cultured cells, the new subunits yielded prominent, typical glutamate- and NMDA-activated currents only when they were in heteromeric configurations with NR1 [43].
  • Taken together, our results suggested that subtoxic NMDA exerts the neuroprotective effect via activation of prosurvival PI-3K/Akt pathway against ischemic brain injury, and BDNF-TrkB signaling and Ca2+-dependent CaM cascade might contribute to NMDA induced activation of PI-3K/Akt pathway [44].
  • NMDA treatment increases active RhoA in dendrites in wild-type hippocampal neurons, but not in mutant neurons [45].
  • We tested the paradigms mentioned in mouse mutants with reduced expression of the NR1 subunit of the NMDA receptor (N = 15) and their wild-type littermates (N = 16) [46].

Analytical, diagnostic and therapeutic context of NMDA


  1. Regulation of NMDA receptors by tyrosine kinases and phosphatases. Wang, Y.T., Salter, M.W. Nature (1994) [Pubmed]
  2. Stress and hippocampal plasticity. McEwen, B.S. Annu. Rev. Neurosci. (1999) [Pubmed]
  3. Activation of NMDA receptors blocks GABAergic inhibition in an in vitro model of epilepsy. Stelzer, A., Slater, N.T., ten Bruggencate, G. Nature (1987) [Pubmed]
  4. Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion. Haberman, R.P., Samulski, R.J., McCown, T.J. Nat. Med. (2003) [Pubmed]
  5. Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway. Yano, S., Tokumitsu, H., Soderling, T.R. Nature (1998) [Pubmed]
  6. Marked prevention of ischemic brain injury by Neu2000, an NMDA antagonist and antioxidant derived from aspirin and sulfasalazine. Gwag, B.J., Lee, Y.A., Ko, S.Y., Lee, M.J., Im, D.S., Yun, B.S., Lim, H.R., Park, S.M., Byun, H.Y., Son, S.J., Kwon, H.J., Lee, J.Y., Cho, J.Y., Won, S.J., Kim, K.W., Ahn, Y.M., Moon, H.S., Lee, H.U., Yoon, S.H., Noh, J.H., Chung, J.M., Cho, S.I. J. Cereb. Blood Flow Metab. (2007) [Pubmed]
  7. Abnormalities of striatal projection neurons and N-methyl-D-aspartate receptors in presymptomatic Huntington's disease. Albin, R.L., Young, A.B., Penney, J.B., Handelin, B., Balfour, R., Anderson, K.D., Markel, D.S., Tourtellotte, W.W., Reiner, A. N. Engl. J. Med. (1990) [Pubmed]
  8. NMDA receptors in the visual cortex of young kittens are more effective than those of adult cats. Tsumoto, T., Hagihara, K., Sato, H., Hata, Y. Nature (1987) [Pubmed]
  9. Mediation of classical conditioning in Aplysia californica by long-term potentiation of sensorimotor synapses. Murphy, G.G., Glanzman, D.L. Science (1997) [Pubmed]
  10. Regulation of NMDA receptor trafficking by amyloid-beta. Snyder, E.M., Nong, Y., Almeida, C.G., Paul, S., Moran, T., Choi, E.Y., Nairn, A.C., Salter, M.W., Lombroso, P.J., Gouras, G.K., Greengard, P. Nat. Neurosci. (2005) [Pubmed]
  11. Memory and addiction: shared neural circuitry and molecular mechanisms. Kelley, A.E. Neuron (2004) [Pubmed]
  12. Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Somjen, G.G. Physiol. Rev. (2001) [Pubmed]
  13. Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Ehlers, M.D., Zhang, S., Bernhadt, J.P., Huganir, R.L. Cell (1996) [Pubmed]
  14. Whisker-related neuronal patterns fail to develop in the trigeminal brainstem nuclei of NMDAR1 knockout mice. Li, Y., Erzurumlu, R.S., Chen, C., Jhaveri, S., Tonegawa, S. Cell (1994) [Pubmed]
  15. Glycine binding primes NMDA receptor internalization. Nong, Y., Huang, Y.Q., Ju, W., Kalia, L.V., Ahmadian, G., Wang, Y.T., Salter, M.W. Nature (2003) [Pubmed]
  16. Novel neural modulators. Boehning, D., Snyder, S.H. Annu. Rev. Neurosci. (2003) [Pubmed]
  17. Potentiation of NMDA receptor currents by arachidonic acid. Miller, B., Sarantis, M., Traynelis, S.F., Attwell, D. Nature (1992) [Pubmed]
  18. AMPA receptor-mediated regulation of a Gi-protein in cortical neurons. Wang, Y., Small, D.L., Stanimirovic, D.B., Morley, P., Durkin, J.P. Nature (1997) [Pubmed]
  19. Neurons containing NADPH-diaphorase are selectively resistant to quinolinate toxicity. Koh, J.Y., Peters, S., Choi, D.W. Science (1986) [Pubmed]
  20. Expression in brain of amyloid precursor protein mutated in the alpha-secretase site causes disturbed behavior, neuronal degeneration and premature death in transgenic mice. Moechars, D., Lorent, K., De Strooper, B., Dewachter, I., Van Leuven, F. EMBO J. (1996) [Pubmed]
  21. Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Woo, T.U., Walsh, J.P., Benes, F.M. Arch. Gen. Psychiatry (2004) [Pubmed]
  22. The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, induces social isolation in rats. Koros, E., Rosenbrock, H., Birk, G., Weiss, C., Sams-Dodd, F. Neuropsychopharmacology (2007) [Pubmed]
  23. Spatial learning without NMDA receptor-dependent long-term potentiation. Saucier, D., Cain, D.P. Nature (1995) [Pubmed]
  24. Regulation of NMDA receptor desensitization in mouse hippocampal neurons by glycine. Mayer, M.L., Vyklicky, L., Clements, J. Nature (1989) [Pubmed]
  25. Kainate-receptor-mediated sensory synaptic transmission in mammalian spinal cord. Li, P., Wilding, T.J., Kim, S.J., Calejesan, A.A., Huettner, J.E., Zhuo, M. Nature (1999) [Pubmed]
  26. Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Lieberman, D.N., Mody, I. Nature (1994) [Pubmed]
  27. Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus. Bashir, Z.I., Alford, S., Davies, S.N., Randall, A.D., Collingridge, G.L. Nature (1991) [Pubmed]
  28. Frequency-dependent involvement of NMDA receptors in the hippocampus: a novel synaptic mechanism. Herron, C.E., Lester, R.A., Coan, E.J., Collingridge, G.L. Nature (1986) [Pubmed]
  29. NMDA receptors and activity-dependent tuning of the receptive fields of spinal cord neurons. Lewin, G.R., Mckintosh, E., McMahon, S.B. Nature (1994) [Pubmed]
  30. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Chatterton, J.E., Awobuluyi, M., Premkumar, L.S., Takahashi, H., Talantova, M., Shin, Y., Cui, J., Tu, S., Sevarino, K.A., Nakanishi, N., Tong, G., Lipton, S.A., Zhang, D. Nature (2002) [Pubmed]
  31. Second-order fear conditioning prevented by blocking NMDA receptors in amygdala. Gewirtz, J.C., Davis, M. Nature (1997) [Pubmed]
  32. An N-methylaspartate receptor-mediated synapse in rat cerebral cortex: a site of action of ketamine? Thomson, A.M., West, D.C., Lodge, D. Nature (1985) [Pubmed]
  33. NMDA-receptor regulation of substance P release from primary afferent nociceptors. Liu, H., Mantyh, P.W., Basbaum, A.I. Nature (1997) [Pubmed]
  34. Potassium conductances in hippocampal neurons blocked by excitatory amino-acid transmitters. Charpak, S., Gähwiler, B.H., Do, K.Q., Knöpfel, T. Nature (1990) [Pubmed]
  35. Multiple conductance channels in type-2 cerebellar astrocytes activated by excitatory amino acids. Usowicz, M.M., Gallo, V., Cull-Candy, S.G. Nature (1989) [Pubmed]
  36. Glutamate release promotes growth of malignant gliomas. Takano, T., Lin, J.H., Arcuino, G., Gao, Q., Yang, J., Nedergaard, M. Nat. Med. (2001) [Pubmed]
  37. Positive allosteric modulation of metabotropic glutamate 5 (mGlu5) receptors reverses N-Methyl-D-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex. Lecourtier, L., Homayoun, H., Tamagnan, G., Moghaddam, B. Biol. Psychiatry (2007) [Pubmed]
  38. Direct inhibitory effect of fluoxetine on N-methyl-D-aspartate receptors in the central nervous system. Szasz, B.K., Mike, A., Karoly, R., Gerevich, Z., Illes, P., Vizi, E.S., Kiss, J.P. Biol. Psychiatry (2007) [Pubmed]
  39. The functional role of the second NPXY motif of the LRP1 beta-chain in tissue-type plasminogen activator-mediated activation of N-methyl-D-aspartate receptors. Martin, A.M., Kuhlmann, C., Trossbach, S., Jaeger, S., Waldron, E., Roebroek, A., Luhmann, H.J., Laatsch, A., Weggen, S., Lessmann, V., Pietrzik, C.U. J. Biol. Chem. (2008) [Pubmed]
  40. Testing NMDA receptor block as a therapeutic strategy for reducing ischaemic damage to CNS white matter. Bakiri, Y., Hamilton, N.B., Káradóttir, R., Attwell, D. Glia (2008) [Pubmed]
  41. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Das, S., Sasaki, Y.F., Rothe, T., Premkumar, L.S., Takasu, M., Crandall, J.E., Dikkes, P., Conner, D.A., Rayudu, P.V., Cheung, W., Chen, H.S., Lipton, S.A., Nakanishi, N. Nature (1998) [Pubmed]
  42. Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Sheng, M., Cummings, J., Roldan, L.A., Jan, Y.N., Jan, L.Y. Nature (1994) [Pubmed]
  43. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Monyer, H., Sprengel, R., Schoepfer, R., Herb, A., Higuchi, M., Lomeli, H., Burnashev, N., Sakmann, B., Seeburg, P.H. Science (1992) [Pubmed]
  44. Subtoxic N-methyl-D-aspartate delayed neuronal death in ischemic brain injury through TrkB receptor- and calmodulin-mediated PI-3K/Akt pathway activation. Xu, J., Zhang, Q.G., Li, C., Zhang, G.Y. Hippocampus (2007) [Pubmed]
  45. Synaptic scaffolding molecule alpha is a scaffold to mediate N-methyl-D-aspartate receptor-dependent RhoA activation in dendrites. Iida, J., Ishizaki, H., Okamoto-Tanaka, M., Kawata, A., Sumita, K., Ohgake, S., Sato, Y., Yorifuji, H., Nukina, N., Ohashi, K., Mizuno, K., Tsutsumi, T., Mizoguchi, A., Miyoshi, J., Takai, Y., Hata, Y. Mol. Cell. Biol. (2007) [Pubmed]
  46. Early auditory sensory processing deficits in mouse mutants with reduced NMDA receptor function. Bickel, S., Lipp, H.P., Umbricht, D. Neuropsychopharmacology (2008) [Pubmed]
  47. NMDA receptors of dentate gyrus granule cells participate in synaptic transmission following kindling. Mody, I., Heinemann, U. Nature (1987) [Pubmed]
  48. Regulation of NMDA receptor phosphorylation by alternative splicing of the C-terminal domain. Tingley, W.G., Roche, K.W., Thompson, A.K., Huganir, R.L. Nature (1993) [Pubmed]
  49. NMDA receptor-mediated K+ efflux and neuronal apoptosis. Yu, S.P., Yeh, C., Strasser, U., Tian, M., Choi, D.W. Science (1999) [Pubmed]
  50. Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition. Zheng, F., Gingrich, M.B., Traynelis, S.F., Conn, P.J. Nat. Neurosci. (1998) [Pubmed]
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