STRUCTURE-ACTIVITY CORRELATION OF THE LETHALITY AND CENTRAL EFFECTS OF SELECTED CARDIAC GLYCOSIDES

¹ Department of Pharmacology, College of Medicine, State Univereity of Iowa, Iowa City, Iowa

Twenty-four-hour toxicity data were obtained for intravenous and intracerebral injections of digitoxin, digoxin, their mono-and bis-digitoxosides and their aglycones in adult male mice. Probit analysis was used to compute potency ratios of all possible pairs of drugs studied. The intravenous data suggested that the toxicity of both the digitoxin-and digoxin-related compounds decreases as time number of sugar residues decreases except for digitoxigenin. The C-12 hydroxyl group made little difference in intravenous toxicity except for the genins, in which the hydroxyl group present in digoxigenin decreased the toxicity. The intracerebral toxicity of these compounds suggest that the presence or absence of digitoxose residues has little, if any, effect on their toxicity by this route, whereas the presence of tile C-12 hydroxyl group increased the toxicity two to three times. In the aforementioned studies, digitoxigenin was, therefore, the most toxic intravenously and the least toxic intracercbrahly, and convulsions always preceded death with this particular agent. The intracerebral toxicities of the 3-epi and 3-keto derivatives of both digoxigenin and digitoxigenin were also obtained. Again, the digoxin-related compounds were more toxic by this route. In both cases, the 3-epi and 3-keto derivatives were less toxic than the parent aglycone.