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NMDA receptor pathways as drug targets

Nature Neuroscience volume 5, pages 1039–1042 (2002)Cite this article

Abstract

Since the mid 1980s, there has been a great deal of enthusiasm within both academia and industry about the therapeutic potential of drugs targeting the NMDA subtype of glutamate receptors. That early promise is just beginning to translate into approvable drugs. Here we review the reasons for this slow progress and critically assess the future prospects for drugs that act on NMDA receptor pathways, including potential treatments for some major disorders such as stroke and Alzheimer's disease, for which effective therapies are still lacking.

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Figure 1: NMDA receptor model showing potential sites for drug action.
Figure 2: A prototypic glutamatergic synapse depicting factors influencing NMDA receptor–mediated neurotransmission.

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References

  1. Watkins, J.C. in The NMDA Receptor (eds. Collingridge, G. L. & Watkins, J. C.) 1–30 (Oxford Univ. Press, New York, 1994).

    Google Scholar 

  2. McBain, C.J. & Mayer, M.L. N-methyl-D-aspartic acid receptor structure and function. Physiol. Rev. 74, 723–760 (1994).

    Article  CAS  Google Scholar 

  3. Das, S. et al. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393, 377–381 (1998).

    Article  CAS  Google Scholar 

  4. Chatterton, J.E. et al. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415, 793–798 (2002).

    Article  CAS  Google Scholar 

  5. Kemp, J.A. & Kew, J.N.C. in Drugs And The Pharmaceutical Sciences Vol. 89 (ed. Leff, P.) 297–321 (Marcel Dekker, New York, 1998).

    Google Scholar 

  6. Williams, K. Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol. Pharmacol. 44, 851–859 (1993).

    CAS  PubMed  Google Scholar 

  7. Kemp, J.A., Kew, J.N.C. & Gill, R. Handbook of Experimental Pharmacology Vol. 141 (eds. Jonas, P. & Monyer, H.) 495–527 (Springer, Berlin, 1999).

    Google Scholar 

  8. Lees, K.R. et al. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators. Lancet 355, 1949–1954 (2000).

    Article  CAS  Google Scholar 

  9. Sacco, R.L. et al. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA 285, 1719–1728 (2001)

    Article  CAS  Google Scholar 

  10. Gotti, B. et al. Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. I. Evidence for efficacy in models of focal cerebral ischemia. J. Pharmacol. Exp. Ther. 247, 1211–1221 (1988).

    CAS  PubMed  Google Scholar 

  11. Kew, J.N.C., Trube, G. & Kemp, J.A. A novel mechanism of activity-dependent NMDA receptor antagonism describes the effect of ifenprodil in rat cultured cortical neurones. J. Physiol. (Lond.) 497, 761–772 (1996).

    Article  CAS  Google Scholar 

  12. Gill, R. et al. Pharmacological characterization of Ro63-1908 (1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-01), a novel sinotype-selective N-methyl-D-aspartate antagonist. J. Pharmacol. Exp. Ther. 302, 940–948 (2002)

    Article  CAS  Google Scholar 

  13. Schwarcz, R.J. Glutamate 2000: old dog, new tricks. Pharmacol. Exp. Ther. 296, 659–662 (2001).

    CAS  Google Scholar 

  14. Parsons, C.G. NMDA receptors as targets for drug action in neuropathic pain. Eur. J. Pharmacol. 429, 71–78 (2001).

    Article  CAS  Google Scholar 

  15. Boyce, S. et al. Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn. Neuropharmacology 38, 611–623 (1999).

    Article  CAS  Google Scholar 

  16. Chizh, B.A., Headley, P.M. & Tzschentke, T.M. NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmacol. Sci. 22, 636–642 (2001).

    Article  CAS  Google Scholar 

  17. Tranquillini, M.E. & Reggiani, A. Glycine-site antagonists and stroke. Expert Opin. Investig. Drugs 8, 1837–1848 (1999).

    Article  CAS  Google Scholar 

  18. Leeson, P.D. & Iversen, L.L. The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. J. Med. Chem. 37, 4053–4067 (1994).

    Article  CAS  Google Scholar 

  19. Chase, T.N., Oh, J.D. & Konitsiotis, S. Antiparkinsonian and antidyskinetic activity of drugs targeting central glutamatergic mechanisms. J. Neurol. 247 (Suppl. 2), 36–42 (2000).

    Google Scholar 

  20. Del Dotto, P. et al. Intravenous amantadine improves levadopa-induced dyskinesias: an acute double-blind placebo-controlled study. Mov. Disord. 16, 515–520 (2001)

    Article  CAS  Google Scholar 

  21. Lederer, R., Radeke, E. & Mondadori, C. Facilitation of social learning by treatment with an NMDA receptor antagonist. Behav. Neural Biol. 60, 220–224 (1993).

    Article  CAS  Google Scholar 

  22. Mondadori, C., Weiskrantz, L., Buerki, H., Petschke, F. & Fagg, G.E. NMDA receptor antagonists can enhance or impair learning performance in animals. Exp. Brain Res. 75, 449–456 (1989).

    Article  CAS  Google Scholar 

  23. Davis, M. The rde of NMDA receptors and MAP kinase in the amygdala in extinction of fear: clinical implications for exposure therapy. Eur. J. Neurosci 16, 395–398 (2002).

    Article  Google Scholar 

  24. Krystal, J.H. et al. NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders. Harv. Rev. Psychiatry 7, 125–143 (1999).

    Article  CAS  Google Scholar 

  25. Tsai, G. & Coyle, J.T. Glutamatergic mechanisms in schizophrenia. Annu. Rev. Pharmacol. Toxicol. 42, 165–179 (2002).

    Article  CAS  Google Scholar 

  26. Tamminga, C. Schizophrenia and glutamatergic transmission. Crit. Rev. Neurobiol. 12, 21–36 (1998).

    Article  CAS  Google Scholar 

  27. Heresco-Levy, U. et al. Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzapine or risperidone in schizophrenia. Am J. Psychiatry 159, 480–482 (2002).

    Article  Google Scholar 

  28. Tsai, G., Yang, P., Chung, L.C., Lange, N. & Coyle, J.T. D-serine added to antipsychotics for the treatment of schizophrenia. Biol. Psychiatry 44, 1081–1089 (1998).

    Article  CAS  Google Scholar 

  29. Mothet, J.P. et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc. Natl. Acad. Sci. USA 97, 4926–4931 (2000).

    Article  CAS  Google Scholar 

  30. Wolosker, H., Blackshaw, S. & Snyder, S.H. Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc. Natl. Acad. Sci. USA 96, 13409–13414 (1999).

    Article  CAS  Google Scholar 

  31. Tang, Y.P. et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 (1999).

    Article  CAS  Google Scholar 

  32. Malayev, A., Gibbs, T.T. & Farb, D.H. Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids. Br. J. Pharmacol. 135, 901–909 (2002).

    Article  CAS  Google Scholar 

  33. Husi, H., Ward, M.A., Choudhary, J.S., Blackstock, W.P. & Grant, S.G. Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat. Neurosci. 3, 661–669 (2000).

    Article  CAS  Google Scholar 

  34. Sheng, M. The postsynaptic NMDA-receptor–PSD-95 signaling complex in excitatory synapses of the brain. J. Cell. Sci. 114, 1251 (2001).

  35. Hardingham, G.E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414 (2002).

    Article  CAS  Google Scholar 

  36. Lu, W. et al. Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243–254 (2001).

    Article  CAS  Google Scholar 

  37. Perin-Dureau, F., Rachline, J., Neyton, J. & Paoletti, P. Mapping the binding site of the neuroprotectant ifenprodil on NMDA receptors. J. Neurosci. 15, 5955–5965 (2002).

    Article  Google Scholar 

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Authors and Affiliations

  1. EVOTEC Neurosciences GmbH, Schackenburgallee 114, Hamburg, D-22525, Germany

    John A. Kemp

  2. Neuroscience Research Centre, Merck Research Laboratories, Essex, Terlings Park, Eastwick Road, Harlow, CM20 2QR, UK

    Ruth M. McKernan

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Correspondence to Ruth M. McKernan.

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Kemp, J., McKernan, R. NMDA receptor pathways as drug targets. Nat Neurosci 5 (Suppl 11), 1039–1042 (2002). https://doi.org/10.1038/nn936

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