Development of the Selective NOS Inhibitors Based on Novel Reaction Mechanism

尽管一氧化氮(NO)在生物系统中发挥着多种作用，但高浓度NO的形成会引起细胞毒性。因此，有必要开发只有在NO产生过多时才能使NO熄灭的化学品。为了开发这类化学品，我们研究了NO与各种杂环化合物的反应，发现N-氨基吡啶高氯酸铵即使在水中也能与NO迅速反应，NO以N_&lt；2O&gt；的形式转化。这一发现表明，NO通过这种反应完全解毒。在有了这一先例的基础上，我们进一步考察了各种N-氨基偶氮芳烃与NO的反应，发现大多数化合物都是很好的NO清除剂。此外，还发现这些化合物与超氧化物反应顺利，从而猝灭了该活性氧物种。因此，N-氨基氮芳烃被发现是NO和超氧化物的良好清除剂，这两种物质在生物系统的氧化损伤中都起着至关重要的作用。此外，我们还发现N-烷基氮杂芳烃季铵盐起到了超氧化物的活化剂作用，氧化裂解C=C双键。

Although nitric oxide (NO) plays a variety of roles in biological systems, formation of NO in high concentration causes cytotoxicity. Thus, it is necessary to develop chemicals which quench NO only when NO is produced excessively. For developing such chemicals, we have investigated the reaction of NO with various heterocyclic compounds and found that N-aminopyridinium perchlorate reacted with NO rapidly even in water and that NO was transformed to the form of N_<2O>. This finding suggests that NO is completely detoxified via this reaction. With this precedent in hand, we further investigated the reaction of various kinds of N-anminoazaaromatics with NO, and found most of all the compounds were good scavengers of NO. Moreover, it was found that these compounds were reacted with superoxide smoothly to quench this active oxygen species. Therefore, N-aminoazaaromatics were found to be good scavengers for both NO and superoxide, both of which play a criticai role in oxidative damage in biological systems. In addition, we also found that N-alkylazaaromatic quaternary salts functioned as activators of superoxide to oxidatively cleavage C=C double bond.