Development of the Selective NOS Inhibitors Based on Novel Reaction Mechanism

虽然一氧化氮（NO）在生物系统中发挥着多种作用，但高浓度一氧化氮的形成会引起细胞毒性。因此，有必要开发只在NO过量产生时才淬灭NO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 -氨基吡啶高氯酸盐即使在水中也能与NO快速反应，并转化为N_<2O>的形式。这一发现表明，通过这种反应，一氧化氮被完全解毒。有了这样的先例，我们进一步研究了各种n -氨基氮杂化物与NO的反应，发现大多数化合物都是良好的NO清除剂。此外，还发现这些化合物能与超氧化物顺利反应以淬灭这些活性氧。因此，n -氨基偶氮化合物被发现是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起着至关重要的作用。此外，我们还发现n -烷基芳族季铵盐作为超氧化物的活化剂氧化裂解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.