Excitatory Amino Acid Antagonists as Novel Anticonvulsants

  • B. Meldrum
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 203)


The convulsant effect of application of dicarboxylic amino acids to the cortex was first reported by Hayashi (1954). This observation suggests that antagonists of excitation induced by amino acid neurotransmitters might be anticonvulsant agents in some forms of epilepsy. Some rather weak and indeterminate anticonvulsant effects of glutamic acid diethyl ester were initially described (Freed and Michaelis, 1978; Freed, 1985). However, following the identification of potent and specific excita- tory amino acid antagonists (Davies et al., 1982) it was shown that compounds that selectively antagonized excitation at the N-methyl-D-aspartate preferring receptor are anticonvulsant, with a potency matching that of the benzodiazepines when administered intracerebroventricularly (Croucher et al., 1982; Chapman et al., 1984). Testing in a wide range of animal models shows that NMDA antagonists provide a novel class of anticonvulsant agent with a broad spectrum of activity roughly equivalent to that of sodium valproate when administered systemically. The further observation that they can protect against ischemic brain damage has strengthened the concept that an excitotoxic mechanism is involved in such damage (Meldrum et al., 1982; Simon et al., 1984).


NMDA Receptor Excitatory Amino Acid Kainic Acid Anticonvulsant Action NMDA Antagonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anderson, E.,Baudry, M., Lynch, G., and Morris, R.G.M., 1985, Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, APV-5, J. Physiol., 367: 31 P.Google Scholar
  2. Chapman, A.G., Collins, J.F., Meldrum, B.S., and Westerberg, E., 1983, Uptak of a novel anticonvulsant compound, 2-amino-7-phosphonoheptanoic [4,5–3H] acid into mouse brain, Neurosci. Lett., 37: 75.Google Scholar
  3. Chapman, A.G., Croucher, M.J., and Meldrum, B.S., 1984, Evaluation of anticonvulsant drugs in DBA/2 mice with sound-induced seizures, Arzneim. Forschung, 34: 1261.Google Scholar
  4. Chapman, A.G., Hart, G.P., Meldrum B.S., Turski, L., and Watkins, J.C., 1985, Anticonvulsant activity of two novel piperazine derivatives with potent kainate antagonist activity, Neurosci. Lett., 55: 325.Google Scholar
  5. Collins, J.F., Dixon, A.J., Badman, G., DeSarro, G., Chapman, A.G., Hart, G.P., and Meldrum, B.S., 1984, Kainic acid derivatives with anticonvulsant activity, Neurosci. Lett., 51: 371.Google Scholar
  6. Connick, J.H., and Stone, T.W., 1985, p-kainic acid inhibits glutamate release from rat brain slices, IRCS Med. Soi., 13: 824.Google Scholar
  7. Croucher, M.J., Collins, J.F., and Meldrum, B.S., 1982, Anticonvulsant action of excitatory amino acid antagonists, Science, 216: 899.PubMedCrossRefGoogle Scholar
  8. Croucher, M.J., Meldrum, B.S., Jones, A.W., and Watkins, J.C., 1984a, y-D-Glutamylaminomethyl-sulphonic acid (GAMS), a kainate and quisqualate antagonist, prevents sound-induced seizures in DBA/2 mice, Brain Res., 322: 111.Google Scholar
  9. Croucher, M.J., Meldrum, B.S., and Collins, J.F., 1984b, Anticonvulsant and proconvulsant properties of a series of structural isomers of piperidine dicarboxylic acid, Neurooharmacology, 23: 467.CrossRefGoogle Scholar
  10. Czuczwar, S.J., Cavalheiro, E.A., Turski, L., Turski, W.A., and Kleinrok, Z., 1985, Phosphonic analogues of excitatory amino acids raise the threshold for maximal electroconvulsions in mice, Neurosci. Res., 3: 86.Google Scholar
  11. Davies, J., Evans, R.H., Jones, A.W., Smith, D.A.S., and Watkins, J.C., 1982, Differential activation and blockade of excitatory amino acid receptors in the mammalian and amphibian central nervous system, Cow. Biochem. Phvsiol., 72C: 211.Google Scholar
  12. Davies, J., Jones, A.W., Sheardown, M.J., Smith, D.A.S., and WatkinsGoogle Scholar
  13. J.C., 1984, Phosphono dipeptides and piperazine derivatives as antagonists of amino acid induced and synaptic excitation in mammalian and amphibian spinal cord, Neurosci. Lett., 52: 79.Google Scholar
  14. De Sarro, G., Meldrum, B.S., and Reavill, C., 1984, Anticonvulsant action of 2-amino-7-phosphonoheptanoic acid in the substantia nigra, Eur. J. Pharmacol., 106: 175.Google Scholar
  15. Dolphin, A.C., and Archer, E.R., 1983, An adenosine agonist inhibits and a cyclic AMP analogue enhances the release of glutamate but not GABA from slices of rat dentate gyrus, Neurosci. Lett., 43: 49.Google Scholar
  16. Evans, R.H., Francis, A.A., Jones, A.W., Smith, D.A.S., and Watkins, J.C.,1982, The effects of a series of m-phosphonic a-carboxylic amino acids on electrically-evoked and excitant amino acid-induced responses in isolated spinal cord preparations, Br. J. Pharmac., 75: 65.Google Scholar
  17. Fagg, G.E., and Lanthorn, T.H., 1985, C1-/Ca,-1--dependent L-glutamate binding sites do not correspond to 2-amino-4-phosphonobutanoate-sensitive excitatory amino acid receptors, Br. J. Pharmacol., 86: 743.Google Scholar
  18. Freed, W.J., and Michaelis, E.K., 1978, Glutamic acid and ethanol dependence, Pharmacol. Biochem. Behay., 8: 509.Google Scholar
  19. Freed, W.J., 1985, Selective inhibition of homocysteine-induced seizures by glutamic acid diethyl ester and other glutamate esters, EDileDsia, 26: 10.Google Scholar
  20. Hablitz, J.J., 1985, Suppression of synaptically evoked epileptiform dischar-ges in the hippocampus by NMDA antagonists, EDileDsia, 26:512. Hayashi, T., 1954, Effects of sodium glutamate on the nervous system,Keio J. Med., 3: 183.Google Scholar
  21. Jones, A.W., Croucher, M.J., Meldrum, B.S., and Watkins, J.C., 1984, Suppression of audiogenic seizures in DBA/2 mice by two new dipeptide NMDA receptor antagonists, Neurosci. Lett., 45: 157.Google Scholar
  22. King, G.L., and Dingledine, R., 1985, Role for N-methyl-D-aspartate receptors in epileptiform bursting, EDileDsia, 26: 509.Google Scholar
  23. Lodge, D., Martin, D., and Aram, J.A., 1985, Comparison of DL-2-amino-5-phosphono-valerate (AP5) and DL-2-amino-7-phosphonoheptanoate (AP7) as anticonvulsants and N-methyl-D-aspartate antagonists in vitro, EDileDsia, 26: 507.Google Scholar
  24. Mayer, M.L., and Westbrook, G.L., 1984, Mixed-agonist action of excitatory amino acids on mouse spinal cord neurones under voltage clamp, J. Physiol. 354: 29.PubMedGoogle Scholar
  25. Meldrum, B.S., Griffiths, T., and Evans, M., 1982, Hypoxia and neuronal hyperexcitability - a clue to mechanisms of brain protection, in: Protection of Tissue Against HvDoxia, A. Wauquier, M. Borgers and W.K. Amery, eds., Elsevier/North Holland, p. 275.Google Scholar
  26. Meldrum, B.S., and Chapman, A.G., 1983, Excitatory amino acids and anti-convulsant drug action, in: Glutamine, Glutamate, and GABA in the Central Nervous System, L. Hertz, E. Kvamme, E. McGeer and A. Schousboe, eds., Alan R. Liss Inc., New York, p. 625.Google Scholar
  27. Meldrum, B.S., Croucher, M.J., Badman, G., and Collins, J.F., 1983a, Anti-epileptic action of excitatory amino acid antagonists in the photosensitive baboon, PaDio DaDio, Neurosci. Lett., 39: 101.Google Scholar
  28. Meldrum, B.S., Croucher, M.J., Czuczwar, S.J., Collins, J.F., Curry, K., Joseph, M., and Stone, T.W., 1983b, A comparison of the anticonvulsant potency of (±)2-amino-5-phosphonopentanoic acid and (+)2-amino-7-phosphonoheptanoic acid, Neuroscience, 9: 925.Google Scholar
  29. Meldrum, B.S., Wardley-Smith, B., Halsey, M., and Rostain, J. C., 1983c, 2-Amino-7-phosphonoheptanoic acid protects against the high pressure neurological syndrome, Eur. J. Pharmacol., 87: 501.Google Scholar
  30. Millan, M.H., Faingold, C.L., and Meldrum, B.S. 1986, Intranigral injection of 2-amino-7-phosphonoheptanoic acid protects against audiogenic seizures in genetically epilepsy prone rats, in: Advances in EDileotologv Google Scholar
  31. P. Wolf, ed., Raven Press, New York. Olney, J.W., Labruyere, J., Collins, J.F., and Curry, K., 1981, D-aminophosphonovalerate is 100 fold more powerful than D-alpha-aminoadipate in blocking N-methylaspartate neurotoxicity, Brain Res., 221:207.Google Scholar
  32. Patel, S., Millan, M.H., Mello, L.M., and Meldrum, B.S., 1986, 2-amino-7-phosphonoheptanoic acid (2-APH) infusion into entopeduncular nucleus protects against limbic seizures in rats, Neurosci. Lett., 64: 226.Google Scholar
  33. Peet, M.J., Leah, J.D., and Curtis, D.R., 1983, Antagonists of synaptic and amino acid excitation of neurons in the cat spinal cord, Brain Res., 266: 83.PubMedCrossRefGoogle Scholar
  34. Perkins, M.N., and Stone, T.W., 1983, Pharmacology and regional variations of quinolinic acid-evoked excitations in the rat central nervous system, J. Pharmacol. ExD. TheraD., 226: 551.Google Scholar
  35. Peterson, D.W., Collins, J.F., and Bradford, H.F., 1983, The kindled amygdala model of epilepsy: anticonvulsant action of amino acid antagonists,Brain Res., 275: 169.Google Scholar
  36. Schwarcz, R., and Meldrum, B.S., 1985, Excitatory amino acid antagonists provide a therapeutic approach to neurological disorders, Lancet, ii: 140.Google Scholar
  37. Simon, R.P., Swan, J.H., Griffiths, T., and Meldrum, B.S., 1984a, Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain, Science, 226: 850.PubMedCrossRefGoogle Scholar
  38. Simon, R.P., Griffiths, T., Evans, M.S., Swan, J.H., and Meldrum, B.S., 1984b, Calcium overload in selectively vulnerable neurons of the hippo-campus during and after ischemia: an EM study in the rat, J. Cerebr. Blood Flow Metab., 4: 350.Google Scholar
  39. Stone, T.W., and Collins, J.F., 1985, ß-kainic acid is not an amino acid antagonist, J. Pharm. Pharmacol., 37: 668.Google Scholar
  40. Swann, J.W., and Brady, R.J., 1985, NMDA antagonists block penicillin-induced after discharges in immature CA3 hippocampal neurons, Eoilevsia, 26:512.Google Scholar
  41. Turski, L., Collins, J.F., and Meldrum, B.S., 1985a, Is p-kainic acid an N-methyl-D-aspartate antagonist?, Brain Res., 336: 162.PubMedCrossRefGoogle Scholar
  42. Turski, L., Schwarz, M., Turski, W.A., Klockgether, T., Sontag, K.H., and Collins, J.F., 1985b, Muscle relaxant action of excitatory amino acid antagonists, Neurosci. Lett., 53: 321.Google Scholar
  43. Turski, L., Cavalheiro, E.A., Turski, W.A., and Meldrum, B.S., 1986, Excitatory neurotransmission within substantia nigra pars reticulata regulates threshold for seizures produced by pilocarpine in rats: effects of intranigral 2-amino-7-phosphonoheptanoate and N-methyl-D-aspartate, Neuroscience, 18: 61.PubMedCrossRefGoogle Scholar
  44. Wardley-Smith, B., and Meldrum, B.S., 1984, Effect of excitatory amino acid antagonists on the high pressure neurological syndrome in rats, Eur. J. Pharmacol., 105: 351.Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • B. Meldrum
    • 1
  1. 1.Neurology DepartmentInstitute of PsychiatryLondonUK

Personalised recommendations