A STUDY ON THE STRUCTURE-ACTIVITY RELATIONSHIP OF THE CARDIOTONIC STEROIDS.
According to the prevailing opinion of today about the structure-activity relationship of cardenolides and bufadienolides, the structural requirements for the characteristic cardiotonic action of these compounds can be summarized as follows: cis-fusion of the C and D rings, hydroxyl groups in positions 3β and 14β, and a five- or six-membered unsaturated lactone ring having β-configuration at C14 (1). Most of the experimental data referred to as evidences supporting this opinion have come, however, from the determination of toxic doses in the whole animal, mainly in the cat, rather than from observations of the action of these compounds in isolated hearts. It follows as a natural consequence that the compounds with a rather weak toxicity have been condemned to be inactive, even if they have a strong cardiotonic action, in spite of the fact that such a kind of compounds may actually be more important from the clinical point of view. For example, the compound like dihydrodigitoxin of which the lactone ring is saturated, and the compound like resibufogenin, which have an epoxide ring between C14 and C15 instead of C14-OH, generally believed to be inactive based on the toxicity data in the cat, have recently been found to be fairly active when tested in the isolated heart (2-3). The authors also found that, different from the above-cited opinion, the presence of 3β-OH is not indispensable for the cardiotonic action of the cardenolides ; 3-epi-digitoxigenin was found to have a definite cardiotonic action upon the isolated frog's heart (See Fig. 8). These findings seem to warrant reexamination of the problem, on the basis of the action of these compounds in the isolated heart. In recent years several adrenocortical steroids and aldosterone antagonists have been reported to be cardiotonic (4-6), despite the fact that their stereochemical structures are essentially different from those of the cardiotonic steroids. In view of these, the authors took up the problem of the cis-fusion of the C and D rings out of the several important points in the structure of cardiotonic steroids as discussed above and reexamined its importance for the specific cardiotonic action using the isolated frog's heart and the heart-lung preparation of the dog.
Synthesis and biological activity of semisynthetic digitalis analogs.
Abstract The cardiac glycosides are one of the most important and widely used groups of drugs in clinical medicine. These vegetable drugs act on the failing heart to produce a marked inotropic effect, and for this purpose they are unrivaled by any synthetic or semisynthetic substitute. The cardiac glycosides are also one of the most toxic groups of substances in general clinical use.
THE ACTION OF SIMPLE LACTONES RELATED TO CARDIAC AGLYCONES
1. Twenty-seven unsaturated lactones related to cardiac aglycones have been studied pharmacologically.

2. β,γ-Angelica lactone, the lactone of 21 -hydroxy-Δ20,22-norcholenic acid, methyl coumalate, and ethyl coumalate, cause systolic standstill of frogs' ventricles when adequate doses are injected into the ventral lymph sac. β-(β-Naphthyl)-Δα,β-butenolide has a suggestive action.

3. In cats, β,υ-angelica lactone and methyl and ethyl coumalates all produce a fall of blood pressure and fail to induce emesis. Electrocardiographically, no ectopic rhythm, multiple foci of impulse formation, various forms of aberrant QRS complexes, and terminal ventricular fibrillation occur as the lethal dose is slowly approached. The evidence in cats is therefore not indicative of any digitalis-like action of the three substances.