Inhibitors of Cyclic Nucleotide Phosphodiesterases

ABSTRACT The interest in drugs which inhibit 3',5′-nucleotide phosphodiesterases is based on the mediatory role attributed to cyclic nucleotides in the intracellular effects of many hormones and neuromediators. Recently, several molecular forms of phosphodiesterase with different substrate specificities and sensitivities to Ca2+ -dependent activation by calmodulin were separated from many mammalian tissues. A new generation of inhibitors acting selectively on the various enzyme forms or preventing their activation by calmodulin was also found. These findings provide a basis for the search of more potent and specific inhibitors which would be useful tools in elucidating the respective role of the different phosphodiesterases in the regulation of cyclic nucleotide levels. The development of such compounds may also provide new therapeutical agents, since physio-pathological alterations of the metabolism of cyclic nucleotides have been reported.