Synthesis and enzymic and ionotropic activity of some new 8-substituted and 6,8-disubstituted derivatives of adenosine cyclic 3',5'-monophosphate

Abstract

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.

Differential effects of cAMP and serotonin on membrane current, action-potential duration, and excitability in somata of pleural sensory neurons of Aplysia

“…All solutions were made immediately before each experiment. Two membrane-permeable and phosphodiesterase-resistant analogues of CAMP were used: either 8-bromo-CAMP (8br-CAMP; Sigma) or 8-4-parachlorophenylthio-CAMP (8pcpt-CAMP; Sigma) (Meyers et al 1974;Miller et al 1980;Simon et al 1973). The 8-pcpt-CAMP analogue was initially dissolved in dimethyl sulfoxide (DMSO; Sigma), but the final concentration of DMSO in the bath never exceeded 0.25% (vol/vol).…”

Inotropic and chronotropic effects of N6‐substituted derivatives of cyclic AMP as assessed in guinea‐pig isolated right atria and papillary muscle

“…We used the bovine myocardial enzyme because of the easy accessibility. However, it is known that the isozyme patterns of the bovine and the guinea-pig heart enzymes are the same; both contain predominantly type II isozymes (George & Graeff, 1981 (Simon et al, 1973) and some of the derivatives were shown to be inhibitors of the bovine heart PDE (Miller et al, 1980), a property which might explain the positive inotropic effects of these compounds. However, as three types of PDE are now known and the positive inotropic effects have been shown to be connected with only one type of the enzymes, i.e.…”

“…However, as three types of PDE are now known and the positive inotropic effects have been shown to be connected with only one type of the enzymes, i.e. PDE III, further studies would have to be undertaken paying due attention to the species differences noted for the inhibition of this enzyme (Simon et al, 1973;Miller et al, 1980).…”