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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

References

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  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]
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  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]
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  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]
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  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]
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  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]
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  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]
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  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]
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