Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1981 Jan;72(1):25–29. doi: 10.1111/j.1476-5381.1981.tb09100.x

Active site-directed alkylation of Na+-K+-ATPase by digitalis sulphonate derivatives of different lipophilicity.

U Fricke, W Klaus, M Rogatti
PMCID: PMC2071539  PMID: 6261865

Abstract

1 Sulphonate derivatives of k-strophanthidin and digitoxigenin were tested as active site-directed labels of Na+-K+-adenosine triphosphatase (Na+-ATPase) from guinea-pig heart. 2 Lipophilicity ranged between P = 93 for strophanthidin-3-tosyloxy-acetate (STA) and P = 3028 for digitoxigenin-3-tosyloxy-acetate (DTA). 3 Although the alkylating moiety of STA and DTA was identical, the reversibility of Na+-K+-ATPase inhibition varied appreciably (82% and 35% respectively). 4 It is concluded that lipophilicity contributes considerably to the irreversible binding of alkylating cardiotonic steroids to myocardial Na+-K+-ATPase.

Full text

PDF
25

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abramson H. N., Cho J. S. Inhibition of sodium- and potassium-dependent adenosine triphosphatase by cardenolide alkylating agents. J Med Chem. 1971 Jun;14(6):509–511. doi: 10.1021/jm00288a011. [DOI] [PubMed] [Google Scholar]
  2. Akera T., Brody T. M. Membrane adenosine triphosphatase. The effect of potassium on the formation and dissociation of the ouabain-enzyme complex. J Pharmacol Exp Ther. 1971 Mar;176(3):545–557. [PubMed] [Google Scholar]
  3. Akera T., Ku D., Tobin T., Brody T. M. The complexes of ouabain with sodium- and potassium-activated adenosine triphosphatase formed with various ligands: relationship to the complex formed in the beating heart. Mol Pharmacol. 1976 Jan;12(1):101–114. [PubMed] [Google Scholar]
  4. Eibl H., Lands W. E. A new, sensitive determination of phosphate. Anal Biochem. 1969 Jul;30(1):51–57. doi: 10.1016/0003-2697(69)90372-8. [DOI] [PubMed] [Google Scholar]
  5. Forbush B., 3rd, Hoffman J. F. Direct photoaffinity labeling of the primary region of the ouabain binding site of (Na+ + K+)-ATPase with [3H]ouabain, [3H]digitoxin and [3H]digitoxigenin. Biochim Biophys Acta. 1979 Aug 7;555(2):299–306. doi: 10.1016/0005-2736(79)90169-x. [DOI] [PubMed] [Google Scholar]
  6. Fricke U., Klaus W. A simple preparation technique for a microsomal Maplus-K-plus-activated ATPase from cardiac tissues of different species. Prep Biochem. 1974;4(1):13–29. doi: 10.1080/00327487408068183. [DOI] [PubMed] [Google Scholar]
  7. Fricke U., Klaus W. Die Haftung verschiedener Cardenolide am Papillarmuskel und einer mikrosomalen ATPase des Meerschweinchenherzens. Naunyn Schmiedebergs Arch Pharmakol. 1971;268(2):200–209. [PubMed] [Google Scholar]
  8. Hegyvary C. Covalent labeling of the digitalis-binding component of plasma membranes. Mol Pharmacol. 1975 Sep;11(5):588–594. [PubMed] [Google Scholar]
  9. Hokin L. E., Mokotoff M., Kupchan S. M. Alkylation of a brain transport adenosinetriphosphatase at the cardiotonic steroid site by strophanthidin-3-haloacetates. Proc Natl Acad Sci U S A. 1966 Apr;55(4):797–804. doi: 10.1073/pnas.55.4.797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Okita G. T., Richardson F., Roth-Schechter B. F. Dissociation of the positive inotropic action of digitalis from inhibition of sodium- and potassium-activated adenosine triphosphate. J Pharmacol Exp Ther. 1973 Apr;185(1):1–11. [PubMed] [Google Scholar]
  11. Peters T., Raben R. H., Wassermann O. Evidence for a dissociation between positive inotropic effect and inhibition of the Na+-K+-ATPase by ouabain, cassaine and their alkylating derivatives. Eur J Pharmacol. 1974 May;26(2):166–174. doi: 10.1016/0014-2999(74)90223-4. [DOI] [PubMed] [Google Scholar]
  12. Rogers T. B., Lazdunski M. Photoaffinity labeling of the digitalis receptor in the (sodium + potassium)-activated adenosinetriphosphatase. Biochemistry. 1979 Jan 9;18(1):135–140. doi: 10.1021/bi00568a021. [DOI] [PubMed] [Google Scholar]
  13. Ruoho A. E., Hokin L. E., Hemingway R. J., Kupchan S. M. Hellebrigenin 3-haloacetates: potent site-directed alkylators of transport adenosinetriphosphatase. Science. 1968 Mar 22;159(3821):1354–1355. doi: 10.1126/science.159.3821.1354. [DOI] [PubMed] [Google Scholar]
  14. Ruoho A., Kyte J. Photoaffinity labeling of the ouabain-binding site on (Na+ plus K+) adenosinetriphosphatase. Proc Natl Acad Sci U S A. 1974 Jun;71(6):2352–2356. doi: 10.1073/pnas.71.6.2352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Tobin T., Akera T., Brody T. M., Taneja H. R. Cardiotonic site directed irreversible inhibition of Na+ + K+-ATPase by 3-azidoacetylstrophanthidin, a photochemical analogue of strophanthidin. Eur J Pharmacol. 1976 Jan;35(1):69–76. doi: 10.1016/0014-2999(76)90301-0. [DOI] [PubMed] [Google Scholar]
  16. Tobin T., Sen A. K. Stability and ligand sensitivity of (3H)ouabain binding to (Na+ + K+)ATPase. Biochim Biophys Acta. 1970 Jan 14;198(1):120–131. doi: 10.1016/0005-2744(70)90040-9. [DOI] [PubMed] [Google Scholar]
  17. Yoda A., Hokin L. E. On the reversibility of binding of cardiotonic steroids to a partially purified (Na+K)-activated adenosinetriphosphatase from beef brain. Biochem Biophys Res Commun. 1970 Aug 24;40(4):880–886. doi: 10.1016/0006-291x(70)90985-x. [DOI] [PubMed] [Google Scholar]
  18. Yoda A. Structue-activity relationships of cardiotonic steroids for the inhibition of sodium- and potassium-dependent adenosine triphosphatase. I. Dissociation rate constants of various enzyme-cardiac glycoside complexes formed in the presence of magnesium and phosphate. Mol Pharmacol. 1973 Jan;9(1):51–60. [PubMed] [Google Scholar]
  19. Yoda A., Yoda S. Association and dissociation rate constants of the complexes between various cardiac aglycones and sodium- and potassium-dependent adenosine triphosphatase formed in the presence of magnesium and phosphate. Mol Pharmacol. 1977 Mar;13(2):352–361. [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES