STUDIES ON THE ALCOHOL DETERRENT AGENT CYANAMIDE

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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.