SYNTHESIS AND QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS OF AZONOMETHYL)-5-BETA-ANDROSTANE-3-BETA,14-BETA-DIOL DERIVATIVES THAT BIND TO NA-ATPASE RECEPTOR(,K+)

A series of 17 beta-(hydrazonomethyl)-5 beta-androstane-3 beta,14 beta -diol derivatives was synthesized and evaluated in the displacement of [H-3]ouabain binding from Na+,K+-ATPase. The data were explored with multiple linear regression and partial least-squares to find possible quantitatives structure-activity relationships. Good correlations were found between binding to the receptor and van der Waals volumes or mo lar refractivities of the 17 beta-hydrazonomethyl substituents and pK( a) values of the compounds. Equivalent results were obtained using the proton affinity (calculated using MOPAC) of the hydrazone residues in stead of experimental pK(a). As basicity or related electronic factors of the substituents explain a significant portion of the observed cha nges in the activity, an ion-pair interaction between a carboxylate re sidue of the enzyme and the protonated 17 beta-hydrazonomethyl group, as postulated by Thomas, plays an important role in the interaction of the ligand to the Na+,K+-ATPase receptor.