A NEW APPROACH TO THE DESIGN OF NOVEL INHIBITORS OF NA-ATPASE - 17-ALPHA-SUBSTITUTED SECO-D 5-BETA-ANDROSTANE AS CASSAINE ANALOGS(,K+)

A new three-dimensional model for the relative binding mode of cassain e 1 and digitoxigenin 2 at the digitalis receptor site is proposed on the basis of the structural and conformational similarities among 1, 2 and its 14,15-seco analogues 3 and 4. Accordingly, the speculation th at also 17 alpha-substituted derivatives of the digitalis 5 beta,14 be ta-androstane skeleton could efficiently bind to the Na+,K+-ATPase rec eptor is put forward and verified through the synthesis of some relate d compounds. The binding affinity shown by 2-(N,N-dimethylamino)ethyl 3 beta,14-dihydroxy-5 beta,14 beta-androstane-17 alpha-acrylate 6 (IC5 0 = 5.89 mu M) and, much more significantly, by the corresponding 14,1 5-seco-14-oxo derivative 9 (IC50 = 0.12 mu M) substantiates the new hy pothesis and opens new prospects to the design of novel inhibitors of Na+,K+-ATPase as potential positive inotropic compounds.