Metabolic formation of iminium species: Metabolism of phencyclidine

Article abstract of DOI:10.1021/jm00347a002

Phencyclidine, 1-(1-phenylcyclohexyl)piperidine (1) is a commonly abused drug which displays both acute and long-term neurotoxic effects. Interest in the possibility that metabolites may contribute to the pharmacological and toxicological effects of phencyclidine has led to the identification of the ring-hydroxylated metabolites 2-4 in several species. Results from previous studies have established that metabolically generated carbinolamines, such as 5, ionize to yield the corresponding iminium ions. These electrophilic species are trapped with nucleophilic cyanide ion as the corresponding α-aminonitriles. With phencyclidine, this sequence would lead to iminium ion 9 and α-aminonitrile 10. Given the potential reactivity of such an iminium species, it could contribute to the reported metabolically dependent covalent binding to proteins observed with radioactive phencyclidine. Therefore, we were prompted to examine the metabolism of phencyclidine in an attempt to trap 9 as the corresponding α-aminonitrile.