RT Journal Article SR Electronic T1 The effect of 16 beta-substitution on the structure and activity of digitoxigenin: is there an additional binding interaction with Na+,K+-ATPase? JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 270 OP 274 VO 29 IS 3 A1 J F Griffin A1 D C Rohrer A1 K Ahmed A1 A H From A1 T Hashimoto A1 H Rathore A1 D S Fullerton YR 1986 UL http://molpharm.aspetjournals.org/content/29/3/270.abstract AB We have studied the basis of the effect of 16 beta-substitution on the structure and activity of digitoxigenin derivatives by examining the crystal structures of these compounds and their inhibitory activity toward the receptor for these drugs, Na+,K+-ATPase. To understand the increase in inhibitory activity of the 16 beta-ester compounds and the decrease in activity of gitoxigenin (16 beta-hydroxydigitoxigenin), both with respect to digitoxigenin, we have compared the observed conformations of gitoxigenin, gitoxigenin 16 beta-formate, and other 16 beta-esters to that of digitoxigenin. Our data do not support the possibility of hydrogen bonding between the 16 beta-hydroxyl of gitoxigenin and the lactone ring, previously suggested to account for the decreased activity of gitoxigenin vis à 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 16 beta-ester moiety has a preferred conformation which may serve to fix the lactone ring in the active conformation. Thus, the increased activity of the 16 beta-esters cannot be explained by altered carbonyl oxygen position and may be related to an additional receptor binding site for the ester moiety.