Inhibition of heart and brain cvclic adenosine 3′,5′-monophosphate phosphodiesterase by new non-steroidic compounds structurally related to natural cardenolides

Abstract

AP 10 and related compounds are non-steroidic analogs of cardenolides which exhibit cardiotonic effects on mammals and amphibians isolated hearts. These synthetic compounds were effective inhibitors of the high affinity cyclic AMP phosphodiesterase of beef heart, rat heart and rat brain. AP 10 was the best inhibitor among them. It was approximately ten times as potent as theophylline and three times less effective than MIX and papaverine. Its affinity for the heart enzyme was eight to ten times higher than for the brain enzyme. The inhibition produced by AP 10 was competitive, reversible and was not reversed by high concentrations of magnesium ions. AP 10 slightly affected the binding of cyclic AMP with specific binding protein, but it had a far lower affinity for the binding sites than cyclic AMP. The possibility that inhibition of the low K m phosphodiesterase by AP 10 and related compounds may contribute to their cardiotonic action is discussed.