1-(4-Aminophenyl)isoquinoline derivatives: Potent inhibitors of calcium-independent and calcium-dependent phosphodiesterases from rat cerebral cortex

Abstract

The effects of a series of 1-(4-aminophenyl)isoquinoline derivatives on the activity of calcium-independent and calcium-dependent phosphodiesterases purified from rat cerebral cortex were examined. Agents were approximately equipotent ( ic 50 values, 0.2 to 25 μM) in inhibiting the calcium-dependent hydrolysis of either cyclic AMP or cyclic GMP, while they were 6–35 times more effective as inhibitors of cyclic AMP hydrolysis when compared to cyclic GMP hydrolysis using the calcium-independent enzyme. The diastereomers of 3-(carbomethoxy)propenamido demonstrated a marked difference in specificity. The cis-isomer was very potent in inhibiting cyclic AMP or cyclic GMP hydrolysis by either enzyme ( ic 50 values, 0.2 to 8 μM) while the trans-isomer was only effective in inhibiting calcium-independent cyclic AMP hydrolysis ( ic 50 values, 2.5 μM). Kinetic analyses of the type of inhibition of the calcium-dependent enzyme revealed that the various agents were competitive inhibitors of cyclic GMP hydrolysis and noncompetitive inhibitors of cyclic AMP hydrolysis. A reverse pattern of inhibition by the isoquinoline derivatives was found using the calcium-independent phosphodiesterase, i. e. noncompetitive inhibition of cyclic GMP while competitive inhibition of cyclic AMP. Inhibition of phosphodiesterases by these agents was also manifest using intact brain slices prepared from rat cerebral cortex. Thus, the agents were found to potentiate forskolin-elicited accumulations of cyclic AMP by 100–700% and increased the half-time for the decline in cyclic AMP following forskolin stimulation from 3 to 6 min.