Cocaine iminium

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. 

Synthesis of antx-a has been done through a ring expansion of cocaine (20), from 1, 5-cyclooctadiene (21) and by intramolecular cyclization between an iminium salt and a nucleophilic carbon atom (22). The structure of antx-a is given in Fig. 1. 

There is speculation that long-term exposure to cyclic tertiary amines such as cocaine, phencyclidine, and phenothiazines may result in biochemical lesions through the formation of reactive metabolites. This premise is supported by the induction of a parkinsonian state by MPTP. Although the initial product of microsomal oxidation is an electrophilic endocyclic iminium intermediate which is thought to be the reactive species primarily responsible for neurotoxicity, there is now evidence that the iminium is in equilibrium with the endocyclic enamine and that the latter is transformed to reactive species. The presence of iminium- detoxifying enzymes in cytosolic and microsomal fractions suggests that rapid inactivation of the iminium... 

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. 

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