Biochemical Pharmacology 2005-09-15

Effect of the digitoxigenin derivative, INCICH-D7, on Na+, K+-ATPase.

Margarita Ramirez, Leonardo Del Valle, Alicia Sanchez-Mendoza, Fermin Alejandro Tenorio, Gabriela Zarco, Gustavo Pastelin

Index: Biochem. Pharmacol. 70(6) , 851-7, (2005)

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Abstract

Compound 14beta,17beta-cycloketoester-3beta-OH androstane (INCICH-D7) is a semisynthetic product of a structural modification of the digitoxigenin molecule. INCICH-D7 has a heterocyclic ketoester type fusion between positions C14 and C17 of the steroid nucleus, which confers this molecule stronger electronegativity than that of digitoxigenin. INCICH-D7 retained positive inotropic effect, with a greater safety margin, when compared to digitoxigenin and ouabain. In this study we have examinated the INCICH-D7 effect on Na+, K+-dependent adenosinetriphosphatase (Na+, K+-ATPase) and compared these results with the ones observed with digitoxigenin and ouabain. The inhibitory effect of INCICH-D7 on Na+, K+-ATPase was five times lower (IC50=4 microM) than that of ouabain (IC50=0.8 microM) and 70 times lower than that of digitoxigenin (IC50=0.06 microM). The inhibitory effect of INCICH-D7 and ouabain on the enzyme was irreversible while digitoxigenin's one was reversible in up to an 80%. Our results indicate that inclusion of the heterocycle between positions C14 and C17 in the digitoxigenin molecule lowers significantly the inhibitory effect on Na+, K+-ATPase and renders the interaction between INCICH-D7 and enzyme irreversible under the studied reaction conditions.