The synthesis of certain new 8-(arythio)- and 8-(alkylthio)-cAMP derivatives and N6-alkyl- and N6-dialkyl-8-(arylthio) and -8-(alkylthio) derivatives of cAMP is reported. On the basis of activation of protein kinase, several N6-alkyl-8-(benzylthio)-cAMP derivatives were selected for evaluation as inotropic agents using cat papillary muscle in vitro. Activity in these studies resulted in the selection of several analogues for in vivo studies in the anesthetized dogs. The best inotropic agent selected on the basis of in vivo studies was N6-butyl-8-(benzylthio)-cAMP (26), which exhibited an increase in blood-flow rate of 85% with no increase in heart rate. A large-scale synthesis of 26 from cAMP is reported via N1-alkylation, followed by a Dimroth rearrangement, reduction, bromination, and nucleophilic displacement via benzyl mercaptan. The N6-alkyl-8-substituted-cAMP derivatives represent a new class of potent inotropic agents. The direct mechanism of action of 26 suggests the possible utility of this cyclic nucleotide to treat clinical myocardial infarction by rapid intravenous infusion.