Mechanisms of blockade of glutamate receptor ionic channels: Paradox of 9-aminoacridine

  • K. H. Kim
  • V. E. Gmiro
  • D. B. Tikhonov
  • L. G. Magazanik
Article

Abstract

9-Aminoacridine and tacrine differ from other channel blockers of NMDA receptors in that their binding prevents the closing of blocked channels and subsequent dissociation of the agonist. Structural determinants of aminoacridine derivatives underlying the blocking mechanism are still unknown. The aim of this study was to elucidate the effects of a dicationic 9-aminoacridine derivative and some other tricyclic compounds on NMDA receptors of rat hippocampal pyramidal neurons. All the compounds under study are voltage-dependent blockers of NMDA channels; their IC50 values recorded at −80 mV vary from 1 to 50 µM. The dicationic derivatives demonstrate the same voltage dependence of the block as the monocationic derivatives. The monoand dicationic tricyclic compounds under study are weak blockers of AMPA receptor channels and differ from adamantane, phenylcyclohexyl and other dicationic derivatives that exhibit greater voltage dependence of the NMDA channel block and are able to induce effective suppression of AMPA channels. We conclude that the mechanisms of action of the tricyclic and dicationic 9-aminoacridine derivatives are different from that of 9-aminoacridine, since these compounds do not prevent closing of the blocked channels. This suggests that the binding site for 9-aminoacridine has specific properties and high selectivity with respect to ligand structure.

Keywords

NMDA NMDA Receptor Memantine Supplement Series Voltage Dependence 

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References

  1. 1.
    Parsons, C.G., Danysz, W., and Quack, G., Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist — a review of preclinical data, Neuropharmacology, 1999, vol. 38, pp. 735–767.PubMedCrossRefGoogle Scholar
  2. 2.
    Johnson, J.W. and Kotermanski, S.E., Mechanism of action of memantine, Curr. Opin. Pharmacol., 2006, vol. 6, pp. 61–67.PubMedCrossRefGoogle Scholar
  3. 3.
    Blanpied, T.A., Boeckman, F.A., Aizenman, E., and Johnson, J.W., Trapping channel block of NMDA-activated responses by amantadine and memantine, J. Neurophysiol., 1997, vol. 77, pp. 309–323.PubMedGoogle Scholar
  4. 4.
    Chen, H.S., and Lipton, S.A., Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism, J. Physiol., 1997, vol. 499, pp. 27–46.PubMedGoogle Scholar
  5. 5.
    Sobolevsky, A. and Koshelev, S., Two blocking sites of amino-adamantane derivatives in open N-methyl-D-aspartate channels, Biophys. J., 1998, vol. 74, pp. 1305–1319.PubMedGoogle Scholar
  6. 6.
    Sobolevsky, A.I., Koshelev, S.G., and Khodorov, B.I., Interaction of memantine and amantadine with agonist-unbound NMDA-receptor channels in acutely isolated rat hipp.ocampal neurons, J. Physiol., 1998, vol. 512, pp. 47–60.PubMedCrossRefGoogle Scholar
  7. 7.
    MacDonald, J.F., Bartlett, M.C., Mody, I., Pahapill, P., Reynolds, J.N., Salter, M.W., Schneiderman, J.H., and Pennefather, P.S., Actions of ketamine, phencyclidine and MK-801 on NMDA receptor currents in cultured mouse hipp.ocampal neurones, J. Physiol., 1991, vol. 432, pp. 483–508.PubMedGoogle Scholar
  8. 8.
    Benveniste, M. and Mayer, M.L., Trapp.ing of glutamate and glycine during open channel block of rat hipp.ocampal neuron NMDA receptors by 9-aminoacridine, J. Physiol., 1995, vol. 483, pp. 367–384.PubMedGoogle Scholar
  9. 9.
    Vorobjev, V.S. and Sharonova, I.N., Tetrahydroaminoacridine blocks and prolongs NMDA receptor-mediated responses in a voltage-dependent manner, Eur. J. Pharmacol., 1994, vol. 253, pp. 1–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Sobolevsky, A.I., Koshelev, S.G., and Khodorov, B.I., Probing of NMDA channels with fast blockers, J. Neurosci., 1999, vol. 19, pp. 10611–10626.PubMedGoogle Scholar
  11. 11.
    Koshelev, S.G. and Khodorov, B.I., Tetrabutylammonium, tacrine, and 9-aminoacridine block open NMDA channels and thus prevent their closing and desensitization, Biol. Membrany (Rus.), 1995, vol. 12, pp. 89–104.Google Scholar
  12. 12.
    Mealing, G.A., Lanthorn, T.H., Small, D.L., Murray, R.J., Mattes, K.C., Comas, T.M., and Morley, P., Structural modifications to an N-methyl-D-aspartate receptor antagonist result in large differences in trapping block, J. Pharmacol. Exp. Ther., 2001, vol. 297, pp. 906–914.PubMedGoogle Scholar
  13. 13.
    Bolshakov, K.V., Gmiro, V.E., Tikhonov, D.B., and Magazanik, L.G., Determinants of trapping block of N-methyl-D-aspartate receptor channels, J. Neurochem., 2003, vol. 87, pp. 56–57.PubMedCrossRefGoogle Scholar
  14. 14.
    Kroemer, R.T., Koutsilieri, E., Hecht, P., Liedl, K.R., Riederer, P., and Kornhuber, J., Quantitative analysis of the structural requirements for blockade of the N-methyl-D-aspartate receptor at the phencyclidine binding site, J. Med. Chem., 1998, vol. 41, pp. 393–400.PubMedCrossRefGoogle Scholar
  15. 15.
    Tikhonov, D.B., Zhorov, B.S., and Magazanik, L.G., Intersegment hydrogen bonds as possible structural determinants of the N/Q/R site in glutamate receptors, Biophys. J., 1999, vol. 77, no. 4, pp.. 1914–1926.PubMedCrossRefGoogle Scholar
  16. 16.
    Vorobjev, V.S., Vibrodissociation of sliced mammalian nervous tissue, J. Neurosci. Methods., 1991, vol. 68, pp. 303–307.CrossRefGoogle Scholar
  17. 17.
    Magazanik, L.G., Buldakova, S.L., Samoilova, M.V., Gmiro, V.E., Mellor, I., and Usherwood, P.R.N., Block of open channels of recombinant AMPA receptors and native AMPA/kainate receptors by adamantane derivatives, J. Physiol., 1997, vol. 505, pp. 655–663.PubMedCrossRefGoogle Scholar
  18. 18.
    Vorobjev, V.S., Sharonova, I.N., and Haas, H.L., A simple perfusion system for patch-clamp studies, J. Neurosci. Methods, 1996, vol. 68, pp. 303–307.PubMedCrossRefGoogle Scholar
  19. 19.
    Woodhull, A.M., Ionic blockage of sodium channels in nerve, J. Gen. Physiol., 1973, vol. 61, pp. 687–708.PubMedCrossRefGoogle Scholar
  20. 20.
    Tikhonov, D.B., Samoilova, M.V., Buldakova, S.L., Gmiro, V.E., and Magazanik, L.G., Voltage-dependent block of native AMPA receptor channels by dicationic compounds, Br. J. Pharmacol., 2000, vol. 129, pp. 265–274.PubMedCrossRefGoogle Scholar
  21. 21.
    Bolshakov, K.V., Tikhonov, D.B., Gmiro, V.E., and Magazanik, L.G., Different arrangement of hydrophobic and nucleophilic components of channel binding sites in N-methyl-D-aspartate and AMPA receptors of rat brain is revealed by channel blockade, Neurosci. Lett., 2000, vol. 291, no. 2, pp. 101–104.PubMedCrossRefGoogle Scholar
  22. 22.
    Bolshakov, K.V., Kim, K.H., Potapjeva, N.N., Gmiro, V.E., Tikhonov, D.B., Usherwood, P.N., Mellor, I.R., and Magazanik, L.G., Design of antagonists for NMDA and AMPA receptors, Neuropharmacology, 2005, vol. 49, pp. 144–155.PubMedCrossRefGoogle Scholar
  23. 23.
    Sobolevskii, A.I. and Khodorov, B.I., Blocker studies of the functional architecture of the NMDA receptor channel, Neurosci. Behav. Physiol., 2002, vol. 32, pp. 157–171.PubMedCrossRefGoogle Scholar
  24. 24.
    Magazanik, L.G., Bolshakov, K.V., Buldakova, S.L., Gmiro, V.E., Dorofeeva, N.A., Lukomskaya, N.Ya., Potapyeva, N.N., Samoilova, M.V., Tikhonov, D.B., Fedorova, I.M., and Frolova, E.V., Structural peculiarities of ionotropic glutamate receptors detected by channel blocking, I.M. Sechenov Rus. Physiol. J. (Rus.), 2000, vol. 86, pp. 1138–1151.Google Scholar
  25. 25.
    Magazanik, L.G., Tikhonov, D.B., Bolshakov, K.V., Gmiro, V.E., Buldakova, S.L., and Samoilova, M.V., Structural studies of ionic channel glutamate receptors and mechanisms of their blocking by organic cations, I.M. Sechenov Rus. Physiol. J. (Rus.), 2001, vol. 87, pp. 1026–1039.Google Scholar
  26. 26.
    Kolesnikova, T.V., Koshelev, S.G., and Khodorov, B.I. Mechanisms of blockade of NMDA channels by local anesthetics, Biol. Membrany (Rus.), 2005, vol. 22, pp. 451–475.Google Scholar
  27. 27.
    Qian, A. and Johnson, J.W., Channel gating of NMDA receptors, Physiol. Behav., 2002, vol. 77, pp. 577–582.PubMedCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2007

Authors and Affiliations

  • K. H. Kim
    • 1
  • V. E. Gmiro
    • 2
  • D. B. Tikhonov
    • 1
  • L. G. Magazanik
    • 1
  1. 1.Sechenov Institute of Evolutionary Physiology and BiochemistryRussian Academy of SciencesSt. PetersburgRussia
  2. 2.Institute of Experimental MedicineRussian Academy of Medical SciencesSt. PetersburgRussia

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