Data currently available suggest that isozymes of adenosine 3',5'-cyclic monophosphate phosphodiesterase may be operative in various tissues. This project involves the synthesis of imidazoles substituted in the 4 and 5 position in order to determine if the structural units of theophylline necessary for inhibitory activity can be incorporated into an agent specific for a given isozyme. These agents and other known inhibitors and stimulators of phosphodiesterase will be studied thoroughly in phosphodiesterase systems from various tissues including brain, adipose, skeletal muscle, heart muscle, liver and a cancer cell culture. These agents will also be studied in detail against a coronary artery preparation in which the phosphodiesterase forms have already been separated and partially purified in our laboratory. Other cell types which have been shown to contain relatively pure enzyme forms in our laboratory will be used as enzyme sources for screening of these compounds. The activity against the various phosphodiesterase systems will then be used to guide synthetic studies directed at agents specific for a given isozyme of phosphodiesterase. The ultimage goal is the design of agents of value against cancer, agents with beneficial CNS activity and agents of value in treatment or study of heart disease.