A series of 17 beta-(hydrazonomethyl)-5 beta-androstane-3, beta,14 beta-diol derivatives was synthesized and evaluated in the displacement of [3H]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 molar refractivities of the 17 beta-hydrazonomethyl substituents and pKa values of the compounds. Equivalent results were obtained using the proton affinity (calculated using MOPAC) of the hydrazone residues instead of experimental pKa. As basicity or related electronic factors of the substituents explain a significant portion of the observed changes in the activity, an ion-pair interaction between a carboxylate residue 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.

A series of digitalis-like compounds, with the lactone ring shifted from the original position through a spacer or replaced by a series of guanylhydrazone substituent-bearing chains, was synthesized and evaluated for inhibition of Na+,K(+)-ATPase and for inotropic activity. The highest Na+,K(+)-ATPase inhibition (IC50) and inotropic activity (EC50) were reached with the vinylogous guanylhydrazone 5 where a cardenolide-like polarized alpha,beta-unsaturated system and a basic guanidino group were both present at the 17 beta-position; for this compound IC50 and EC50 values were comparable to or higher than those of Thomas' parent guanylhydrazone 1, digitoxigenin, and digoxin. A substantial improvement of the desired positive inotropic activity versus the toxic arrhythmogenic concentration was not reached within this series; only a slightly better therapeutic index can be envisaged for compounds 5 and 4, even though, for the latter, to the detriment of potency, presumably because of a weaker interaction with the receptor, due to the lack of a cardenolide-like polarized system.

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Synthesis, Cardiotonic Activity, and Structure-Activity Relationships of 17β-Guanylhydrazone Derivatives of 5β-Androstane-3β,14β-diol Acting on the Na + ,K + -ATPase Receptor.-Among a series of title compounds, e.g. (I)-(V), compounds (II) and (III) show improved biological activity in comparison to parent compound (I), lactone (VI), and digitalis cardiac glycosides digoxin and digitoxigenin. However, a substantial improvement of the desired positive inotropic activity versus the toxic arrhythmogenic concentration is not achieved. -(CERRI, A.; SERRA, F.; FERRARI, P.; FOLPINI, E.; PADIANI, G.; MELLONI, P.; J.