A NEW CLASS OF NITRIC OXIDE-GENERATING ACTIVATORS OF SOLUBLE GUANYLATE-CYCLASE

Derivatives of diazetidine-di-N-oxyl, comprising a new class of compounds capable of generating nitric oxide (NO), have been studied. Nonenzymatic NO generation by these agents involves an essentially novel mechanism, decomposition at physiological pH values. Effects of the compounds under-investigation on the activity of soluble guanylate cyclase (GC) from human platelets have been evaluated. Four of the seven studied diazetidine-di-N-oxyl derivatives showed a clear-cut correlation between the GC-stimulating activity and the ability to undergo decomposition with concomitant MO formation. Maximal effect was observed with 3-bromo-4-methyl-3,4-tetramethylene-diazetidine-di-N-oxyl, which also exhibited a spasmolytic activity comparable to that of nitroglycerine. The results indicate that these compounds, which can under certain conditions generate NO and thereby activate GC, show promise for the development of new vasodilating agents. Derivatives of 1,2-diazetidine-1,2-di-N-oxyl offer considerable scope in this field.