Advertisement

Neurochemical Research

, Volume 11, Issue 11, pp 1609–1621 | Cite as

Histrionicotoxins: Effects on binding of radioligands for sodium, potassium, and calcium channels in brain membranes

  • T. Lovenberg
  • J. W. Daly
Original Articles

Abstract

A series of eight histrionicotoxins and two synthetic analogs inhibit binding of [3H]batrachotoxinin B to sites on voltage dependent sodium channels in brain membranes. Perhydrohistrionicotoxin (IC50 0.33 μM) and octahydrohistrionicotoxin (IC50 1.2 μM) are comparable in activities to potent local anesthetics. Histrionicotoxin (IC50 17 μM) and the other histrionicotoxins are much less potent. The histrionicotoxins also inhibit binding of [3H]phencyclidine to putative potassium channels in brain membranes. Histrionicotoxin (IC50 15 μM) and the other histrionicotoxins are much more potent than perhydrohistrionicotoxin (IC50 200 μM), but are at least 200-fold less potent than phencyclidine. The histrionicotoxins enhance binding of [3H]nitrendipine to sites on calcium channels in brain membranes, with the exception of perhydrohistrionicotoxin, which inhibits binding. Structure activity relationships at these channel sites and at the sites for noncompetitive blockers on the nicotinic acetylcholine receptor channel (AChR) complex differ. The histrionicotoxins are more potent at the sites on the AChR complex than at sites on other channels with the exception of perhydrohistrionicotoxin, which has comparable potency at the AChR complex and sodium channels.

Keywords

Calcium Channel Sodium Channel Structure Activity Relationship Nicotinic Acetylcholine Nicotinic Acetylcholine Receptor 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Albuquerque, E. X., Aguayo, L. G., Warnick, J. E., Weinstein, H., Glick, S. D., Maayani, S., Ickowicz, R. K., andBlaustein, M. P. 1981. The behavioral effects of phencyclidines may be due to their blockade of potassium channels. Proc. Natl. Acad. Sci. USA 78:7792–7796.Google Scholar
  2. 2.
    Albuquerque, E. X., Tsai, M.-C., Aronstam, R. S., Eldefrawi, A. T., andEldefrawi, M. E. 1980. Sites of action of phencyclidine. II. Interaction with the ionic channel of the nicotinic receptor. Mol. Pharmacol. 18:167–178.Google Scholar
  3. 3.
    Aronstam, R. S., Eldefrawi, A. T., andEldefrawi, M. E. 1980. Similarities in the binding sites of the muscarinic receptor and the ionic channel of the nicotinic receptor. Biochem. Pharmacol. 29:1311–1314.Google Scholar
  4. 4.
    Aronstam, R. S., King, Jr., C. T., Albuquerque, E. X., Daly, J. W., andFeigl, D. M. 1985. Binding of [3H]perhydrohistrionicotoxin and [3H]phencyclidine to the nicotinic receptor-ion channel complex ofTorpedo electroplax. Inhibition by histrionicotoxins and derivatives. Biochem. Pharmacol. 34:3037–3047.Google Scholar
  5. 5.
    Betz, H. 1982. Interaction of histrionicotoxin with the putative nicotinic acetylcholine receptor of the chick visual system. Neurosci. Lett. 33:153–158.Google Scholar
  6. 6.
    Bolger, G. T., Rafferty, M. F., andSkolnick, P. 1986. Dihydropyridine calcium antagonist binding is enhanced in rat brain by phencyclidine and pharmacologically related compounds. J. Neurochem., in press.Google Scholar
  7. 7.
    Creveling, C. R., McNeal, E., Daly, J. W., andBrown, G. B. 1983. Batrachotoxin-induced depolarization and [3H]batrachotoxinin-A 20α-benzoate binding in a vesicular preparation from guinea pig cerebral cortex: Inhibition by local anesthetics. Mol. Pharmacol. 23:350–358.Google Scholar
  8. 8.
    Creveling, C. R., McNeal, E. T., Lewandowski, G. A., Rafferty, M., Harrison, E. H., Jacobson, A. E., Rice, K. C., andDaly, J. W. 1985. Local anesthetic properties of opioids and phencyclidines: Interaction with the voltage-dependent, batrachotoxin binding site in sodium channels. Neuropeptides 5:353–356.Google Scholar
  9. 9.
    Daly, J. W. 1985. Effects of alkaloids on ion transport. Pages 121–133, in Proceedings of the Naito Symposium on Natural Products and Biological Activity, Tokyo Press, Toyko.Google Scholar
  10. 10.
    Daly, J. W., Karle, I., Myers, C. W., Tokuyama, T., Walters, J. A., andWitkop, B. 1971. Histrionicotoxins: Roentgen-ray analysis of the novel allenic and acetylenic spiroalkaloids isolated from a Colombian frog,Dendrobates histrionicus. Proc. Natl. Acad. Sci. USA 68:1870–1875.Google Scholar
  11. 11.
    Daly, J. W., Witkop, B., Tokuyama, T., Nishikawa, T., andKarle, I. L. 1977. Gephyrotoxins, histrionicotoxins and pumiliotoxins from the neotropical frogDendrobates histrionicus. Helv. Chim. Acta 60:1128–1140.Google Scholar
  12. 12.
    Eldefrawi, A. T., Eldefrawi, M. E., Albuquerque, E. X., Oliveira, A. C., Mansour, N., Adler, M., Daly, J. W., Brown, G. B., Burgermeister, W., andWitkop, B. 1977. Perhydrohistrionicotoxin: A potential ligand for the ion conductance modulator of the acetylcholine receptor. Proc. Natl. Acad. Sci. USA 74:2172–2176.Google Scholar
  13. 13.
    Eldefrawi, M. E., Aronstam, R. S., Bakry, N. M., Eldefrawi, A. T., andAlbuquerque, E. X. 1980. Activation, inactivation, and desensitization of acetylcholine receptor channel complex detected by binding of perhydrohistrionicotoxin. Proc. Natl. Acad. Sci. USA 77:2309–2313.Google Scholar
  14. 14.
    Elliott, J., Dunn, S. M. J., Blanchard, S. G., andRaftery, M. A. 1979. Specific binding of perhydrohistrionicotoxin toTorpedo acetylcholine receptor. Proc. Natl. Acad. Sci. USA 76:2576–2579.Google Scholar
  15. 15.
    Heidmann, T., Oswald, R. E., andChangeux, J.-P. 1983. Multiple sites of action for noncompetitive blockers on acetylcholine receptor rich membrane fragments fromTorpedo marmorata. Biochemistry 22:3112–3127.Google Scholar
  16. 16.
    Hollingsworth, E. B., McNeal, E. T., Burton, J. L., Williams, R. J., Daly, J. W., andCreveling, C. R. 1985. Biochemical characterization of a filtered synaptoneurosome preparations from guinea pig cerebral cortex: Cyclic adenosine 3′:5′-monophosphate-generating systems, receptors, and enzymes. J. Neurosci. 5:2240–2253.Google Scholar
  17. 17.
    Lapa, A. J., Alpuquerque, E. X., Sarvey, J. M., Daly, J., andWitkop, B. 1975. Effects of histrionicotoxin on the chemosensitive and electrical propertiesof skeletal muscle. Exp. Neurol. 47:558–578.Google Scholar
  18. 18.
    Marangos, P. J., Patel, J., Muller, C., andMartino, A. M. 1982. Specific calcium antagonist binding sites in brain. Life Sci. 31:1575–1585.Google Scholar
  19. 19.
    McNeal, E. T., Creveling, C. R., andDaly, J. W. 1980. Cyclic AMP-generating systems in cell-free preparations from guinea pig cerebral cortex: Loss of adenosine and amine responsiveness due to low levels of endogenous adenosine. J. Neurochem. 35:338–342.Google Scholar
  20. 20.
    Postma, S. W., andCatterall, W. A. 1984. Inhibition of binding of [3H]batrachotoxinin-A 20-α-benzoate to sodium channels by local anesthetics. Mol. Pharmacol. 25:219–227.Google Scholar
  21. 21.
    Spivak, C. E., andAlbuquerque, E. X. 1982. Dynamic properties of the nicotinic acetylcholine receptor ionic channel complex: Activation and blockade. Pages 323–357,in Hanin, I., andGoldberg, A. M. (eds.), Progress in Cholinergic Biology: Model Cholinergic Synapses. Raven Press, New York.Google Scholar
  22. 22.
    Spivak, C. E., Maleque, M. A., Oliveira, A. C., Masukawa, L., Tokuyama, T., Daly, J. W., andAlbuquerque, E. X. 1982. Actions of histrionicotoxins at the ion channel of the nicotinic acetylcholine receptor and the voltage sensitive ion channels of muscle membranes Mol. Pharmacol. 21:351–361.Google Scholar
  23. 23.
    Tokuyama, T., andDaly, J. W. 1983. Steroidal alkaloids (batrachotoxins and 4β-hydroxybatrachotoxin), “indole alkaloids” (calycanthine and chimonanthine) and a piperidinyldipyridine alkaloid (noranabasamine) in skin extracts from the Colombian poison-dart frogPhyllobates terribilis (dendrobatidae). Tetrahedron 39:41–47.Google Scholar
  24. 24.
    Vignon, J., Vincent, J. P., Bidard, J. N., Kamenka, J. M., Genetste, P., Monier, S., andLazdunski, M. 1982. Biochemical properties of the brain phencyclidine receptor. Eur. J. Pharmacol 81:531–542.Google Scholar

Copyright information

© Plenum Publishing Corporation 1986

Authors and Affiliations

  • T. Lovenberg
    • 1
  • J. W. Daly
    • 1
  1. 1.Laboratory of Bioorganic ChemistryNational Institute of Arthritis, Diabetes, Digestive and Kidney Diseases National Institutes of HealthBethesda

Personalised recommendations