Development of the Selective NOS Inhibitors Based on Novel Reaction Mechanism

虽然一氧化氮（NO）在生物系统中起着多种作用，但高浓度NO的形成会引起细胞毒性。因此，有必要开发仅在过量产生NO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-氨基吡啶高氯酸盐与NO反应迅速，甚至在水中也能转化为N_2<2O>。这一发现表明，NO是通过这种反应完全解毒。在此基础上，我们进一步研究了各种N-氨基氮杂芳烃与NO的反应，发现它们大多数都是NO的良好清除剂，并且发现这些化合物与超氧阴离子的反应非常平稳，能够猝灭活性氧。因此，发现N-氨基氮杂芳烃是NO和超氧化物的良好清除剂，这两者在生物系统的氧化损伤中起关键作用。此外，我们还发现N-烷基氮杂芳香族季铵盐具有超氧阴离子活化剂的作用，能氧化断裂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.