Key result
Hydroindene amidinohydrazones with the same absolute configuration as natural cardenolides showed inotropic effects and NKA inhibition similar to digoxin but with lower potency, without affecting cardiac rhythm.
Why the study?
Do synthesized hydroindene amidinohydrazones exert inotropic effects without affecting cardiac rhythm in preclinical models?
Do synthesized hydroindene amidinohydrazones exert inotropic effects without affecting cardiac rhythm in preclinical models?
Synthesized hydroindene amidinohydrazones demonstrate inotropic activity without chronotropic effects, potentially through selective inhibition of the human alpha2beta1 Na+,K+-ATPase isozyme.
Several hydroindenic derivatives (7a-methyl-2,3,5,6,7,7a-hexahydro-1H-indenes), bearing an amidinohydrazone at C-5 and different moieties at C-1, have been synthesized and evaluated for their inotropic and chronotropic effects on right- and left-guinea-pig-atria activity. Three of them showed the same profile as digoxin, although with lower potency. The effect on Na(+),K(+)-ATPase (NKA) was also evaluated for these three compounds, observing that two of them, with the same absolute configuration as natural cardenolides, are also NKA inhibitors, while the compound with the opposite configuration lacks such an effect. More interestingly, both active compounds act without affecting the cardiac rhythm. This could be related to the selective inhibition of the human alpha2beta1 isozyme (associated with the inotropic effect) with respect to the alpha1beta1 isozyme (associated with the maintenance of basal ionic levels in the cell and the toxic effect of cardenolides).
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Sevillano et al. (2001) studied this question. Hydroindene amidinohydrazones vs. Digoxin was evaluated on Inotropic and chronotropic effects, and Na+,K+-ATPase (NKA) inhibition. Hydroindene amidinohydrazones with the same absolute configuration as natural cardenolides showed inotropic effects and NKA inhibition similar to digoxin but with lower potency, without affecting cardiac rhythm.
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