Cyanamide is used clinically outside the United States as an alcohol deterrent drug. Bioactivation of cyanamide produces the metabolite nitroxyl (HNO), which acts as an inhibitor of aldehyde dehydrogenase (AIDH) via thiol modification. The resulting increase in blood acetaldehyde levels are accompanied by unpleasant symptoms that discourage continued use of alcohol. That cyanamide also produces cyanide upon bioactiviaton has restricted clinical approval in the United States. However, the efficacy and lower toxicity compared to existing approved alcohol deterrent agents suggests that HNO donors may serve to improve pharmacotherapy of alcohol abuse. Primary amine diazeniumdiolates (NONOates) having the general structure [RNHN(O)NO]- can be designed to be either NO or HNO donors. Furthermore, these compounds are amenable to prodrug-formation via O2- derivatization with protecting groups. This application focuses on development of HNO-donating NONOates that can be used as AIDH inhibitors but with the potential for fewer side effects compared to cyanamide or disulfiram.
The specific aims of this application are 1) to synthesize and characterize a series of HNO releasing NONOates and prodrugs and 2) to analyze the pharmacological proficiency for AIDH inhibition and potential toxicity of HNO-donating NONOates. Completion of these aims will establish whether HNO donating NONOates can function as viable alternatives to cyanamide in the treatment of alcoholism and alcohol abuse. Nitroxyl (HNO) is a reactive, physiologically-relevant compound that has potential to positively impact diseases as diverse as heart failure and alcoholism. HNO is the active metabolite of cyanamide, which is used outside the United States for the treatment of chronic alcohol dependence. Due to the toxic byproducts of cyanamide, new HNO-donating compounds are desired to serve as alternative pharmacological agents for the treatment of alcohol abuse.
| Flores-Santana, Wilmarie; Salmon, Debra J; Donzelli, Sonia et al. (2011) The specificity of nitroxyl chemistry is unique among nitrogen oxides in biological systems. Antioxid Redox Signal 14:1659-74 |
| Andrei, Daniela; Salmon, Debra J; Donzelli, Sonia et al. (2010) Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class. J Am Chem Soc 132:16526-32 |
