Calcium-independent activation of calcium ion dependent cyclic nucleotide phosphodiesterase by synthetic compounds: quinazolinesulfonamide derivatives.
Quinazolinesulfonamides are synthetic compounds which calcium-independently stimulate Ca2+-dependent cyclic nucleotide phosphodiesterase. As this activation was observed with 2,4-dipiperidino-6-quinazolinesulfonamides but not with 4-piperidino-6-quinazolinesulfonamides, the activation seems to be dependent on the piperidine residue at the 2 and 4 position of the quinazoline ring, and the extent of hydrophobicity of each compound was thus enhanced. 2,4-Dipiperidino-6-quinazolinesulfonamide activates Ca2+-dependent phosphodiesterase in the absence of Ca2+-calmodulin (CaM). These quinazolinesulfonamides did not further enhance the activity of Ca2+-dependent phosphodiesterase activated by the Ca2+-CaM complex. These compounds are also potent inhibitors of cyclic AMP and GMP phosphodiesterases. CaM antagonists such as N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), its derivatives, and chlorpromazine and prenylamine inhibited selectively the quinazolinesulfonamide-induced activations of the phosphodiesterase. These quinazolinesulfonamides, in a high concentration, had only a slight stimulatory effect on myosin light chain kinase activity. All these findings suggest that the quinazolinesulfonamides are calcium-independent activators of Ca2+-dependent phosphodiesterase and they are proving to be useful tools for the study of CaM and phosphodiesterase, in vitro.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism*; D001792:Blood Platelets / Q000201:enzymology; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D011799:Quinazolines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D002147:Calmodulin; D011799:Quinazolines; D013449:Sulfonamides; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D002118:Calcium