MOLECULAR PHAR.MACOWGY, 48:184-188 (1995). ACCELERATED COMMUNICATION Potent and Selective Inhibition of Nitric Oxide-Sensitive Guanylyl

In brain and other tissues, nitric oxide (NO) operates as a diffusible second messenger that stimulates the soluble form of the guanylyl cyclase enzyme and so elicits an accumulation of cGMP in target cells. Inhibitors of NO synthesis have been used to implicate NO in a wide spectrum of physiological and patho-physiological mechanisms in the nervous system and else-where. The function of cGMP in most tissues, however, has remained obscure. We have now identified a compound, i H-[i,2,4]oxadiazolo[4,3-a}quinoxalin-i-one (ODQ), that potently and selectively inhibits NO-stimulated guanylyl cyclase activity. In incubated slices of cerebellum, ODQ reversibly inhibited the NO-dependent cGMP response to glutamate receptor agonists (IC50 20 nM) but did not affect NO synthase activity. The compound did not affect synaptic glutamate receptor function, as assessed in hippocampal slices, nor did it chemically mac