Norcocaine nitroxide

Cocaine may be TV-demethyl ate d by the cytochrome P450 system to produce an active metabolite, norcocaine. Further breakdown produces A-hydroxynorcocaine and norcocaine nitroxide. Further metabolism produces a highly reactive free radical that is thought to be responsible for the hepatotoxicity observed in cocaine users.1... 

Immobilization- and Hypothermia-Induced Myocardial Damage. 655 Norcocaine Nitroxide-lnduced Hepatotoxicity.657... 

The hepatotoxicity of cocaine is known to be associated with its N-oxidative pathway. Cocaine is first hf-demethylated to norcocaine, followed by oxidation to N-hydroxynorcocaine and then to norcocaine nitroxide. Norcocaine nitroxide is the active metabolite. Rauckman et al. (1984) presented a scheme of nonooxygenase-catalyzed reduction of... 

Possible entities for participation in the CNS effects of 1 are the drug itself, norcocaine 2, norcocaine nitroxide 3, and an iminium ion generated from 1. To test the potential involvement of ET, we investigated the electrochemical characteristics (reduction and/or oxidation) of cocaine, norcocaine, and nitroxide 3. Relevent prior literature is also discussed. 

Cocaine 1 hydrochloride (Mallinckrodt Chemical Works) was converted to the free base in the electrochemical cell by addition of NaOH (0 125 M), Norcocaine 2 (used as oil) was prepared by the method of Lazer et al. hydrochloride, mp 114-115 C, lit. mp 115-117 C m/z(EI) 289 (2-HCl). Norcocaine nitroxide 3 was obtained as an oil from 2 using m-chloroperbenzoic acid m/z(EI) 304(3) the sample also contained some m-chlorobenzoic acid. Di- and tri-n-butylamines (Eastman and K and K Laboratories) were distilled from caustic pellets. For electrochemical analysis the solvents acetonitrile (Chempure or Aldrich) and dimethyl-formamide (DMF) (Aldrich) were used without further purification. The electrolyte was tetraethylammonium perchlorate (TEAP) (G.F. Smith Chemical Co.). 

Norcocaine nitroxide 3 reduced at about -0.5 V in aprotic media (Table 1) in an irreversible fashion with Epp/2 = 70-80 mV (HMDE), but no reaction was observed with Pt as the working electrode. The magnitude of the reduction potential may be related to delocalization of the radical on both nitrogen and oxygen as in 7a-c, as well as on the carbonyl group of the methyl ester (transannular interaction). Similarly, various... 

This report deals with application of the ET concept to the mode of action of cocaine and its metabolites. Possible agents for participation in electrochemical transformations are cocaine, norcocaine, norcocaine nitroxide, and cocaine iminium. Electroreduction of cocaine nitroxide occurred in the energetically favorable range of -0.48 to -0.55 V. Electrooxidation was observed at the indicated values cocaine (1.29 V), norcocaine (1.39 V), and norcocaine nitroxide (0.75 V). Relevant prior literature is discussed. 

Norcocaine 2, the demethylated metabolite of cocaine 1, is detected soon after administration of the parent drug. This transformation be the initial step in a metabolic sequence leading to the observed toxicity. Microsomes in the liver and brain further oxidize 2 to the. nitroxide which may be intimately involved in a variety of free... 

The hydroxylamine derivative is metabolically formed from norcocaine". Since reduction of nitroxides in protic solvents yields this derivative in a reversible manner , the transformation evidently does not pertain to our irreversible case, although it may be applicable in vivo. A futile redox cycle involving 3 and the hydroxylamine form has been proposed to account for the hepatotoxicity of V. Irreversibility may be due to 1,5-intramolecular nucleophilic attack by the oxygen anion 5 on the methyl ester carbonyl. Related nitrone species are known to undergo similar intramolecular interaction with unsaturation . The absence of reoxidation of the anion observed in solution might not pertain in vivo due to the active site binding. 

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