17 alpha-O-(aminoalkyl)oxime derivatives of 3 beta,14 beta-dihydroxy-5 beta-androstane and 3 beta-hydroxy-14-oxoseco-D-5 beta-androstane as inhibitors of Na+,K+-ATPase at the digitalis receptor

The synthesis and binding affinities to the digitalis Na+,K+-ATPase recepto r of a series of 3 beta ,14 beta -dihydroxy-5 beta -androstane and 3 beta - hydroxy-14-oxoseco-D-5 beta -androstane derivatives bearing a 17 alpha-(ami noalkoxy)imino chain are reported; some derivatives were also studied for t heir inotropic activity. Our recently proposed model of interaction of mole cules with the digitalis receptor was used to design these compounds. On th at basis, the possibility to design novel potent inhibitors of Na+,K+-ATPas e without being constrained by the stereochemistry of the classical digital is skeleton in the D-ring region was predicted. The binding affinities of t he most potent compounds in the two series, (EZ)-17 alpha-{2-[(2-aminoethox y)imino]ethyl}-5 beta -androstane-3 beta ,14 beta -diol (6f) and (EZ)-3 bet a -hydroxy-17 alpha-{2-[(2-aminoethoxy)imino]ethyl}-14,15-seco-5 beta -andr ostan-14-one (24c) are higher than that of the potent natural compound digi toxigenin, despite the unusual alpha -exit of the substituent in position 1 7 of 6f or the disruption of the D-ring in 24c. These results further suppo rt the validity of our recently proposed model of binding at the digitalis receptor. Results of the inotropic tests on guinea pig atrium deserve furth er investigation on the pharmacological profile of these derivatives.