Several 8-substituted derivatives of cyclic AMP were tested for their effects on α-amylase release. None of the 8-substituted compounds were more active than N 6, O 2′ -dibutyrl- or N 6-monobutyrl adenosine 3′,5′-,monophosphate in causing α-amylase release. The rat parotid was foudn to contain a high (105 μM) and a low (1.15 μM) K m cyclic AMP phosphodiesterase activity. All of the 8-substituted cyclic AMP compounds inhibited the hydrolysis of 1 μM cyclic AMP. However, there was only a partial correlation between the ability to cause α-amylase release and inhibit cyclic AMP hydrolysis. Extracts of parotid tissue contained a cyclic AMP-dependent protein kinase activity. None of the compounds were as effective as cyclic AMP in activating the protein kinase. As in the case of inhibition of cyclic AMP hydrolysis, the ability of the 8-substituted cyclic AMP compounds to increase protein kinase activity did not correlate with their effects on α-amylase release. It is concluded that factors in addition to the in vitro inhibition of cyclic AMP hydrolysis and activation of protein kinase are important in determining the net result of the 8-substituted cyclic AMP compounds on parotid gland function. These additional factors might include differences in the rate of uptake and differences in rats of conversion to compound with modified activity.