The effect of 16β-substitution on the structure and activity of digitoxigenin: Is there an additional binding interaction with Na+, K+-ATPase?

J. F. Griffin, D. C. Rohrer, K. Ahmed, A. H. From, T. Hashimoto, H. Rathore, D. S. Fullerton

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Abstract

We have studied the basis of the effect of 16β-substitution on the structure and activity of digitoxigenin derivatives by examining the crystal structures of these compounds and their inhibitory activity towards the receptor for these drugs, Na+, K+-ATPase. To understand the increase in inhibitory activity of the 16β-ester compounds and the decrease in activity of gitoxigenin (16β-hydroxydigitoxigenin), both with respect to digitoxigenin, we have compared the observed conformations of gitoxigenin, gitoxigenin 16β-formate, and other 16β-esters to that of digitoxigenin. Our data do not support the possibility of hydrogen bonding between the 16β-hydroxyl of gitoxigenin and the lactone ring, previously suggested to account for the decreased activity of gitoxigenin vis a vis digitoxigenin, but, rather, suggest that the decreased activity may be due to an intramolecular hydrogen bond between the hydroxyls on C-14 and C-16 and an unusual D-ring conformation which combine to alter the carbonyl oxygen of the lactone ring away from the putative active position. In contrast, the 16β-ester moiety has a preferred conformation which may serve to fix the lactone ring in the active conformation. Thus, the increased activity of the 16β-esters cannot be explained by altered carbonyl oxygen position and may be related to an additional receptor binding site for the ester moiety.

Original languageEnglish (US)
Pages (from-to)270-274
Number of pages5
JournalMolecular Pharmacology
Volume29
Issue number3
StatePublished - 1986
Externally publishedYes

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