Changes in cardiac glycoside activity produced by aminosugar addition

In anesthetized dogs, structure activity relationships among three cardiotonic compounds were determined by comparing the cardiovascular effects of digotoxigenin (the genin) to digitoxigenin-galactose (a genin-neutral sugar combination) and to digitoxigenin-aminogalactose (ASI-222, a genin-aminosugar combination) using either bolus i.v. injections or constant i.v. infusion. We recorded the effects of these drugs upon cardiac rate, mean blood pressure, left ventricular dP/dt, cardiac index, systolic time intervals, tension-time index, therapeutic index, ventricular excitability and the ventricular refractory period. The addition of an aminosugar group to digitoxigenin or an amine group to galactose-digitoxigenin results in an agent with greater ability to reduce heart rate and to increase cardiac contractility and cardiac index without affecting the tension-time index. Moreover, the addition of an amino group significantly increased the therapeutic index and ventricular refractory period but reduced the toxic index (lethal dose/toxic) when compared to the neutral-sugar cardenolide and genin. Our data indicate that such a substitution confers greater potency, prolongs the duration of activity and results in a compound with greater therapeutic index.