STUDIES ON THE ALCOHOL DETERRENT AGENT CYANAMIDE

酒精类威慑剂的生物作用机制 由于二硫胺和三聚氰胺是被抑制的一种关键酶 负责乙醇的代谢，即乙醛 脱氢酶(ALDH)。这种机制在分子水平上的研究 级别应该提供一个知识库，该知识库最终可以导致 更好的治疗癌症药物的设计和合成 酗酒。 最近，我们发现氧化酶，如过氧化氢酶 和肝脏的细胞色素P-450酶，激活氰胺 成为一种有效的ALDH抑制剂，并将其转化为氰化物。我们 假设一种常见的中间体N-羟基氰胺是 这种酶促氧化的产物，然后自发地 分解成氰化物和氮氧基，后者是可能的 ALDH的抑制剂。氰胺抑制ALDH的作用机制 提出了由初步数据支持的(氮氧基)。示踪剂 旨在确凿地证明氮氧基途径的研究 将进行氰胺生成氰化物的实验。按顺序 为了进一步验证这一机制，一系列氰胺类似物 而在生物作用上模仿三聚氰胺的同系物将 被合成并针对ALDH进行测试。特别关注的是 在那些释放氮氧基但不释放氰化物的同系物上。

The mechanism of biological action of alcohol deterrent agents such as disulfiram and cyanamide is by inhibition of a key enzyme responsible for the metabolism of ethanol, viz., aldehyde dehydrogenase (AlDH). Studies of such mechanisms at the molecular level should provide a knowledge base that can lead ultimately to the design and synthesis of better drugs for the treatment of alcoholism. Recently, we discovered that oxidizing enzymes, such as catalase and the cytochrome P-450 enzymes of the liver, activate cyanamide to a potent inhibitor of AlDH, and also convert it to cyanide. We postulated that a common intermediate, N-hydroxycyanamide, is the product of this enzymatic oxidation, which then spontaneously decomposes to cyanide and nitroxyl, and latter being the possible inhibitor of AlDH. A mechanism for AlDH inhibition by cyanamide (nitroxyl) supported by preliminary data has been propose. Tracer studies intended to conclusively document the pathway for nitroxyl and cyanide formation from cyanamide will be performed. In order to further validate this mechanism, a series of cyanamide analogs and congeners that mimic cyanamide in its biological action will be synthesized and tested against AlDH. Particular focus will be on those congeners that liberate nitroxyl but not cyanide.