THE ACTIVE GROUPINGS IN THE MOLECULES OF CINO- AND MARINO-BUFAGINS AND CINO- AND VULGARO-BUFOTOXINS

¹ From the Lilly Research Laboratories, Eli Lilly and Company, Indianapolis

In order to ascertain which chemical groupings known to exist in the molecules of cino- and marino-bufagin are responsible for the characteristic actions, a pharmacological study of the derivatives of the two substances has been carried out. The lactone ring and the double bonds appear to be of utmost importance because a breaking of this ring or saturation with hydrogen is followed by practically a complete loss of their specific action on the heart. In this respect the bufagins are similar to the genins of plant cardiac glucosides. The acid radical (acetic or formic) attached to a hydroxyl group is almost equally indispensable since its removal results in such a great reduction of action that the effect on the heart becomes either nil or slight. Modification of the OH groups, that is, acetylation, chlorination, or oxidation, diminishes but does not abolish the typical cardiac action, particularly in mammals.

Cino- and vulgaro-bufotoxin appear to owe their activity to the corresponding bufagins. However, their hydrolytic products, suberic acid, arginine, and cino- and vulgaro-bufagiene, all possess little or no action, because the acid radical (acetic) is split off from the bufagins during the reaction. Cino-bufagiene is the only substance that has a trace of action in the cat with large doses.

Generally speaking, the side effects of these derivatives—local, pressor, and augmentation of the movements of smooth-muscle organs—are influenced in the same way as the cardiac action. However, acetylation of cino- or marino-bufagin intensifies the local action on the tongue. The presence of suberic acid in the molecules of bufotoxins probably accounts for the relatively higher emetic action as compared with that of the bufagins, since this acid alone causes vomiting in pigeons.