Structure-Activity Relationship at the Glycosidic Moiety of Digitalis Compounds as Found in Tests with Na/K-Atpase Isoforms from Cardiac Muscle of Guinea-Pig and Man

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Abstract
The glycosidic moiety plays an important role in the pharmacokinetic and pharmacodynamic behaviour of cardiac glycosides like digitoxin and digoxin. Their tridigitoxoside side chain becomes slowly removed in the animal body and hence delays the inactivation of the drugs by epimerization and conjugation of the C3β-hydroxy group to which the glycosidic side chain is attached.1,2 In addition, the glycosidic component affects the kinetics of the glycoside interaction with the receptor enzyme, i.e., the Na/K-ATPase, by influencing both the lag time for the onset of action and the half-life time for the length of action. 3The determination of the association and dissociation rate constants has shown that these parameters of receptor kinetics are modulated by the structure of the monoside bound proximately to the steroid moiety.4 Although repeatedly analysed, the attempts of modelling the structure-activity relationships (SAR) have not reached general significance and predictive capacity5 as required for the safe utilization in synthetic work. The lack of such information, appears to be due to the conformational flexibility of the glycoside side chain.6,7

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