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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007317-02
Application #
3111100
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1989-01-01
Project End
1991-12-31
Budget Start
1990-01-01
Budget End
1990-12-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Pharmacy
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
DeMaster, E G; Redfern, B; Nagasawa, H T (1998) Mechanisms of inhibition of aldehyde dehydrogenase by nitroxyl, the active metabolite of the alcohol deterrent agent cyanamide. Biochem Pharmacol 55:2007-15
Conway, T T; DeMaster, E G; Lee, M J et al. (1998) Prodrugs of nitroxyl and nitrosobenzene as cascade latentiated inhibitors of aldehyde dehydrogenase. J Med Chem 41:2903-9
Shirota, F N; Stevens-Johnk, J M; DeMaster, E G et al. (1997) Novel prodrugs of cyanamide that inhibit aldehyde dehydrogenase in vivo. J Med Chem 40:1870-5
Shirota, F N; Goon, D J; DeMaster, E G et al. (1996) Nitrosyl cyanide, a putative metabolic oxidation product of the alcohol-deterrent agent cyanamide. Biochem Pharmacol 52:141-7
Nagasawa, H T; DeMaster, E G; Goon, D J et al. (1995) Carbethoxylating agents as inhibitors of aldehyde dehydrogenase. J Med Chem 38:1872-6
Nagasawa, H T; Kawle, S P; Elberling, J A et al. (1995) Prodrugs of nitroxyl as potential aldehyde dehydrogenase inhibitors vis-a-vis vascular smooth muscle relaxants. J Med Chem 38:1865-71
Fukuto, J M; Gulati, P; Nagasawa, H T (1994) Involvement of nitroxyl (HNO) in the cyanamide-induced vasorelaxation of rabbit aorta. Biochem Pharmacol 47:922-4
Nagasawa, H T; Yost, Y; Elberling, J A et al. (1993) Nitroxyl analogs as inhibitors of aldehyde dehydrogenase. C-nitroso compounds. Biochem Pharmacol 45:2129-34
Fukuto, J M; Hszieh, R; Gulati, P et al. (1992) N,O-diacylated-N-hydroxyarylsulfonamides: nitroxyl precursors with potent smooth muscle relaxant properties. Biochem Biophys Res Commun 187:1367-73
Lee, M J; Elberling, J A; Nagasawa, H T (1992) N1-hydroxylated derivatives of chlorpropamide and its analogs as inhibitors of aldehyde dehydrogenase in vivo. J Med Chem 35:3641-7

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