TY - JOUR
T1 - The effect of 16β-substitution on the structure and activity of digitoxigenin
T2 - Is there an additional binding interaction with Na+, K+-ATPase?
AU - Griffin, J. F.
AU - Rohrer, D. C.
AU - Ahmed, K.
AU - From, A. H.
AU - Hashimoto, T.
AU - Rathore, H.
AU - Fullerton, D. S.
PY - 1986
Y1 - 1986
N2 - 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.
AB - 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.
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M3 - Article
C2 - 3005835
AN - SCOPUS:0022632827
SN - 0026-895X
VL - 29
SP - 270
EP - 274
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 3
ER -