Effects of 8-substituted adenosine 3',5'-monophosphate derivatives on high Km phosphodiesterase activity

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Abstract
Most of 21 8-substituted cyclic AMP (cAMP) derivatives inhibited competitively the hydrolysis of cAMP by partially purified high Km phosphodiesterase from hog brain cortex, which had 1 active site at high concentrations of cAMP (0.3-4.0 mM). The Ki value for the 8-substituted alkylamino-cAMP derivative decreased with increasing unbranched carbon chain of the substituent, and a minimum value was obtained in the case of 8-octylamino-cAMP. The Ki value, however, increased gradually as the substituent of derivative became longer than that of 8-octylamino-cAMP. The similar phenomenon was observed in the 8-substituted alkylthio-cAMP. The standard affinity for cAMP of the high Km phosphodiesterase was 5.0 kcal/mol, which was calculated from Km. The standard affinity for 8-hexylthio-cAMP, which inhibited most strongly the enzyme activity, was 7.2 kcalmol. The difference (2.2 kcal/mol) between the standard affinity for cAMP and that for 8-hexylthio-cAMP seems to be based on the partial affinity for the substituent (hexylthio group) of the active site on the enzyme or its neighborhood. A characteristic similar interrelation between substituent length of derivatives and their inhibitory effect on the enzyme activity was observed similarly in 2 different series of derivatives, 8-substituted alkylamino-cAMP and alkylthio-cAMP. The results may indicate the characteristic structure at the active site of the enzyme or its neighborhood.