In spite their reduced therapeutic index, digitalis-type drugs continue being used for treating diseases such as congestive heart failure and chronic atrial fibrillation. Thanks to the development of several methods, their structural determination has been feasible, so, structural modifications have been worked out to modulate their toxicity. Several reports realizes that efficacy for these digitalis-type drugs lies on the electronegativity centered on the steroidal moiety (D-ring) generated by either lactone and hydroxyl substituents attached to the steroidal moiety. In this work, we report how electronegativity, and so structural conformation, does modify their pharmacological properties, e.g., inotropism and safety margin. Thus, we evaluated a series of eleven drugs derived from digitoxigenin, named -OH, -Lac, D-01, D-02, D-03, D-07, D-14, D-15, D-20, D-21 and D-22, with groups that substitute both lactone and hydroxyl groups on the steroidal D-ring. Electronegativity and conformational energy were determined by Duhamm's method. The pharmacological evaluation for these drugs was accomplished in guinea pigs isolated hearts (according to the model proposed by Langendorff) and dog's isolated heart (as established by Starling's in vivo model). The results may suggest that digitalis-like action lies on the substituents attached to the D-ring. Positive inotropic effect and therapeutic index are related with increases in electronegativity as well with decreases in rotational and translational energies; therefore, these molecular properties have such importance for the digitalis efficacy.