Abstract
1. Tetraponerines are a group of alkaloids occurring in the venoms of ants belonging to the genus Tetraponera. Eight compounds had been isolated and their structures elucidated, but their mechanisms of action had not yet been reported. We have studied the actions of several of these tetraponerines on vertebrate neuromuscular, ganglionic, and brain nicotinic acetylcholine receptors (nAChRs) using a variety of techniques including muscle contracture, cultured cell functional assays, neuronal patch clamping, and radioligand binding methods.
2. Potency for inhibition of the frog muscle carbachol-elicited contracture increased as the carbon 9 side chain alkyl group was increased in length to 10–12 carbons, then decreased when the chain was 18-carbons long. Potency differences between T-7 and T-8, which differ only in the stereochemistry of the carbon pentyl side chain were rather small. Quaternization of either N atom in a T-8 analog bearing a 10-carbon length alkyl substituent did not greatly affect potency for inhibition of the muscle response; thus the ionized form is an active form of this tetraponerine.
3. T-7 inhibited the nicotine-stimulated efflux of 86Rb from cultured PC12 cells, which primarily express alpha3–beta4 ganglionic type nicotinic receptors. T-8 blockade of BTX-sensitive and insensitive neuronal nAChRs, as studied by patchclamp recordings from cultured rat brain neurons, was also consistent with a noncompetitive type of inhibition.
4. T-7 displaced binding of the nAChR ion channel binding ligand thienylcyclophenidyl (TCP), an analog of PCP, to Torpedo neuromuscular type receptors. The affinity of the TCP binding site for T-7 did not depend upon the desensitization state of the receptor.
5. We conclude that the tetraponerines act at a site on nAChRs different from the ACh binding site which is probably located within the ion channel.
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REFERENCES
Aistrup, G. L., Marszalec, W., and Narahashi, T. (1999). Ethanol modulation of nicotinic acetylcholine receptor currents in cultured cortical neurons. Mol. Pharmacol. 55:39–49.
Albuquerque, E. X., Pereira, E. F. R., Castro, N. G., Alkondon, M., Reinhardt, S., Schröder, H., and Maelicke, A. (1995). Nicotinic receptor function in the mammalian central nervous system. Ann. NY Acad. Sci. 757:48–71.
Albuquerque, E., Alkondon, M., Pereira, E. F. R., Castro, N. G., Schrattenholz, A., Barbosa, C. T. F., Bonfante-Cabaracas, R., Aracava, Y., Eisenberg, H. M., and Maelicke, A. (1997). Properties of neuronal nicotinic acetylcholine receptors: Pharmacological characterization and modulation of synaptic function. J. Pharmacol. Exp. Ther. 280:1117–1136.
Aronstam, R. S., Edwards, M. W., Daly, J. W., and Albuquerque, E. X. (1988). Interactions of piperidine derivatives with the nicotinic cholinergic receptor complex from Torpedo electric organ. Neurochem. Res. 13:171–176.
Braekman, J. C., Daloze, D., Pasteels, J. M., Van Hecke, P., Declercq, J. P., Sinnwell, V., and Francke, W. (1987). Tetraponerine-8, an alkaloidal contact poison in a Neoguinean pseudomyrmecine ant, Tetraponera sp. Z. Naturforsch. 42C:627–630.
Daly, J. W., Garraffo, H. M., and Spande, T. F. (1999). Alkaloids from amphibian skins. In (Pelletier, S. W. (ed.) Alkaloids: Chemical and Biological Perspectives, Elsevier Science, Oxford, pp. 1–161.
Eldefrawi, M. E., Aronstam, R. S., Bakry, N. M., Eldefrawi, A. T., and Albuquerque, E. S. (1980). Activation, inactivation, and desensitization of acetylcholine receptor channel complex detected by binding of perhydrohistrionicotoxin. Proc. Natl. Acad. Sci. U.S.A. 77:2309–2313.
Flores, C. M., Rogers, S. W., Pabreza, L. A., Wolfe, B., and Kellar, K. J. (1992). A subtype of nicotinic cholinergic receptor is composed of alpha4 and beta2 subunits and is up-regulated by chronic nicotine treatment. Mol. Pharmacol. 41:11–37.
Garrafo, H. M., Spande, T. F., Jain, P., Kaneko, T., Jones, T. H., Blum, M. S., Musthak, Ali, T. M., Snelling, R. R., Esbell, L. A., Roberson, H. G., and Daly, J. W. (2001). Ammonia chemical ionization tandem mass spectrometry in structural determination of alkaloids. II. Tetraponerines from pseudomyrmecine ants. Rapid Commun. Mass Spectrom. 15:1409–1415.
Kem, W. R. (1988). Pyridine alkaloid distribution in the hoplonemertines. Hydrobiologia 156:145–151.
Kem, W. R., Abbott, B. C., and Coates, R. M. (1971). Isolation and structure of a hoplonemertine toxin. Toxicon 9:15–22.
Kem, W. R., Mahnir, V. M., Papke, R., and Lingle, C. (1997). Anabaseine is a potent agonist upon muscle and neuronal alpha-bungarotoxin sensitive nicotinic receptors. J. Pharmacol. Exp. Ther. 283:979–992.
Kem, W. R., Scott, K. N., and Duncan, J. H. (1976). Hoplonemertine worms—A new source of pyridine neurotoxins. Experietia 32:684–686.
Leclercq, S., Braekman, J. C., Daloze, D., and Pasteels, J. M. (2000). The defensive chemistry of ants. Prog. Chem. Org. Nat. Prod. 79(part II):115–229.
Leclercq, S., Charles, S., Daloze, D., Braekman, J. C., Aron, S., and Pasteels, J. M. (2001). Absolute configuration of anabasine from Messor and Aphaenogaster ants. J. Chem. Ecol. 27:945–952.
Lukas, R. J., and Cullen, M. J. (1988). An isotopic rubidium ion efflux assay for the functional characterization of nicotinic acetylcholine receptors on clonal cell lines. Anal. Biochem. 175:212–218.
Macours, P., Braekman, J. C., and Daloze, D. (1995). Concise asymmetric synthesis of (+)-and (-)-tetraponerine-8, (+)-and (-)-tetraponerine-7, and their ethyl homologues. A correction of the structures of tetraponerine-3, and-7. Tetrahedron 51:1415–1428.
Marks, M. J., and Collins, A. C. (1982). Characterization of nicotine binding in mouse brain and comparison with the binding of alpha-bungarotoxin and quinuclindinyl benzilate. Mol. Pharmacol. 22:554–564.
Marszalec, W., Aistrup, G. L., and Narahashi, T. (1999). Ethanol-nicotine interactions at α-bungarotoxin-insensitive nicotinic acetylcholine receptors in rat cortical neurons. Alcohol. Clin. Exp. Res. 23:439–445.
Marszalec, W., and Narahashi, T. (1993). Use-dependent pentobarbital block of kainate and quisqualate currents. Brain Res. 608:7–15.
Merlin, P., Braekman, J. C., and Daloze, D. (1991). Stereoselective total synthesis of (±)-tetraponerine-8. Tetrahedron 47:3805–3816.
Merlin, P., Braekman, J. C., Daloze, D., and Pasteels, J. M. (1988). Tetraponerines, toxic alkaloids in the venom of the neo-Guinean Pseudomyrmecine ant Tetaponera sp. J. Chem. Ecol. 14:517–527.
Plehiers, M., Helforn, S., Ekelmans, D., Leclercq, S., Sangermano, M., Braekman, J. C., and Daloze, D. (2000). An expeditious synthesis of (±)-decahydro-5H-dipyrrolo[1,2-a:1′,2′-c]pyrimidine-5-carbonitrile: A formal synthesis of (±)-tetraponerines-1,-2,-5, and-6. Can. J. Chem. 78:1030–1034.
Renson, B., Merlin, P., Daloze, D., and Braekman, J. C. (1994). Biosynthesis of tetraponerine-8, a defence alkaloid of the ant Tetraponera sp. Can. J. Chem. 72:105–109.
Tursch, B., Braekman, J. C., and Daloze, D. (1976). Arthropod alkaloids. Experientia 32:401–536.
Yeh, J. Z., Narahashi, T., and Almon, R. R. (1975). Characterization of neuromuscular blocking action of piperidine derivatives. J. Pharmacol Exp. Ther. 194:373–383.
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Kem, W.R., Wildeboer, K., LeFrancois, S. et al. Nicotinic Receptor Inhibition by Tetraponera Ant Alkaloids. Cell Mol Neurobiol 24, 535–551 (2004). https://doi.org/10.1023/B:CEMN.0000023628.65936.a7
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DOI: https://doi.org/10.1023/B:CEMN.0000023628.65936.a7