CARDENOLIDE ANALOGS. V. CARDIOTONIC ACTIVITY OF SEMISYNTHETIC ANALOGS OF DIGITOXIGENIN

¹ Department of Pharmacy, University of Sydney, Sydney, Australia

The ability of a series of new cardenolide analogs to produce a positive inotropic effect in isolated, driven, guinea-pig atria was determined. The analogs were all derivatives of digitoxigenin and were prepared by replacing the C17-lactone ring with a series of open-chain moieties. A range of potency was observed varying from compounds with activities comparable to that of the parent molecule, digitoxigenin, to those which were inactive or which produced a negative inotropic effect. All of the active compounds produced toxic effects at doses close to those which produced maximum stimulant effect. Structure-activity relationships were defined and a model was proposed for that part of the receptor which accommodates the C17 side chain of cardiotonic steroids of the digitalis type. It was hypothesized that the receptor contains an anionic site which lies within a cleft of defied dimensions. High activity was associated with those molecules which poscess a 17 side chain which can fit within the cleft and interact with the anionic site either by a single anion-cation association or by a two-point attachment involving a weak interaction between a partial positive charge on the side chain and the anionic site of the receptor reinforced by the formation of a hydrogen bond. The results were compared with previously published results which described the ability of the analogs to inhibit Na⁺, K⁺-activated adenosine triphosphatase. An apparent difference between ability to inhibit the enzyme and ability to induce a positive inotropic effect was observed.