Cardenolide analogs. An explanation for the usual properties of AY 22241

AY 22241 (AY) was compared with digitoxigenin with respect to effects on myocardial contractility and inhibition of Na+, K+-ATPase. Ay was less potent than digitoxigenin but otherwise showed the same type of rapid onset and rapid reversal of activity usually associated with genins. Since AY is a glycoside, its behaviour was regarded as anomalous since glycosides usually show both slow onset and slow reversal of activity. Attempts were made to account for the genin-like properties of AY in terms of the model for the digitalis receptor proposed by Thomas et al. (1974a,b). It is suggested that the low potency and genin-like properties of AY may be due to the fact that the steroid is attached to the lactone through the carbon atom that is alpha to the carbonyl group. This feature could result in non-alignment of the sugar residue with the sugar binding site and might also reduce the effectiveness of the interaction of the steroid moiety with its binding site. A notable feature of AY toxicity was its extremely rapid progression to irreversible fibrillation.