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

Derivatives of diazetidine-di-N-oxyl, comprising a new class of compou nds capable of generating nitric oxide (NO), have been studied. Nonenz ymatic NO generation by these agents involves an essentially novel mec hanism, decomposition at physiological pH values. Effects of the compo unds under-investigation on the activity of soluble guanylate cyclase (GC) from human platelets have been evaluated. Four of the seven studi ed diazetidine-di-N-oxyl derivatives showed a clear-cut correlation be tween the GC-stimulating activity and the ability to undergo decomposi tion with concomitant MO formation. Maximal effect was observed with 4 -methyl-3,4-tetramethylene-diazetidine-di-N-oxyl, which also exhibited a spasmolytic activity comparable to that of nitroglycerine. The resu lts 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-ox yl offer considerable scope in this field.