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Decahydroquinoline alkaloids: Noncompetitive blockers for nicotinic acetylcholine receptor-channels in pheochromocytoma cells andTorpedo electroplax

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Abstract

In pheochromocytoma PC12 cells, (+)-cis-decahydroquinoline 195A (5-methyl-2-propyl-cis-decahydroquinoline) and (+)-perhydro-cis-decahydroquinoline 219A (2,5-dipropyl-cis-decahydroquinoline) inhibit carbamylcholine-elicited sodium flux with IC50 values of 1.0 and 1.5 μM, respectively. Both of these decahydroquinolines appear to enhance desensitization, although apparent lack of complete removal of (+)-perhydro-cis-219A by washing complicates interpretation of the effects of that agent. A series of cis- and trans-decahydroquinolines with substituents in the 2- and 5-position also exhibit structure-dependent inhibition of carbamylcholine-elicited sodium flux in PC12 cells and all of the decahydroquinolines inhibit binding of the noncompetitive blocking agent [3H]perhydrohistrionicotoxin to muscle-type nicotinic acetylcholine receptor-channels in membranes fromTorpedo electroplax. The Ki values in electroplax membranes range from 1.4 to 7.9 μM, making these alkaloids comparable in potencies to the histrionicotoxins. Potencies are increased 2- to 3-fold in the presence of an agonist, carbamylcholine. The profile of activities are similar in PC12 cells and electroplax membranes. The cis- and trans-decahydroquinolines represent another class of noncompetitive blockers for acetylcholine receptor-channels with similar activity for both muscle-type and ganglionic type nicotinic receptors.

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Authors and Affiliations

  1. Laboratory of Bioorganic Chemistry, National Institutes of Health, 20892, Bethesda, Maryland

    John W. Daly, Yukio Nishizawa & William L. Padgett

  2. Faculty of Science, Osaka City University, Osaka, Japan

    Takashi Tokuyama

  3. Department of Chemistry, Rensselaer Polytechnic Institute, 12180-3590, Troy, New York

    Patrick J. McCloskey, Liladhar Waykole & Arthur G. Schultz

  4. Department of Pharmacology and Toxicology, Medical College of Georgia, 30912-3368, Augusta, Georgia

    Robert S. Aronstam

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  1. John W. Daly
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Daly, J.W., Nishizawa, Y., Padgett, W.L. et al. Decahydroquinoline alkaloids: Noncompetitive blockers for nicotinic acetylcholine receptor-channels in pheochromocytoma cells andTorpedo electroplax. Neurochem Res 16, 1207–1212 (1991). https://doi.org/10.1007/BF00966697

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