STUDIES ON THE ALCOHOL DETERRENT AGENT CYANAMIDE

酒精威慑剂的生物作用机制， 双硫仑和氰胺是通过抑制一种关键酶 负责乙醇的代谢，即，醛 脱氢酶（AlDH）。 在分子水平上研究这种机制 一级应提供一个知识基础， 设计和合成更好的药物来治疗 酒精中毒 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，激活氨腈 转化为AlDH的有效抑制剂，并将其转化为氰化物。 我们 假设一个共同的中间体，N-羟基氰胺，是 这种酶促氧化的产物，然后自发地 分解为氰化物和硝酰基，后者是可能的 AlDH抑制剂。 氨腈抑制AlDH的机理 （硝酰基）已被初步数据所支持。 示踪剂 旨在最终证明硝酰基途径的研究 并进行由氨腈形成氰化物。 为了 为了进一步验证这种机制， 和同系物，模仿氰氨在其生物作用， 合成并针对AlDH进行测试。 将特别侧重 那些释放硝酰基但不释放氰化物的同系物。

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.