Metabolism of a dopamine D-4-selective antagonist in rat, monkey, and humans: Formation of a novel mercapturic acid adduct

3-{[4-(4-Chlorophenyl)piperazin-1-yl]-methyl}-1H-pyrrolo-2,3-beta-pyridine (L-745,870) is a dopamine D-4 selective antagonist that has been studied as a potential treatment for schizophrenia, with the expectation that it woul d not exhibit the extrapyramidal side effects often observed with the use o f classical antipsychotic agents. The metabolism of L-745,870 in vivo was i nvestigated in the rat, rhesus monkey, and human using liquid chromatograph y-tandem mass spectrometry and/or NMR techniques in conjunction with radioc hemical detection. In all three species, two major metabolic pathways were identified, namely N-dealkylation at the substituted piperazine moiety and the formation of a novel mercapturic acid adduct. It is proposed that the l atter biotransformation process involves the formation of an electrophilic imine methide intermediate, analogous to that produced from 3-methyl indole . This report appears to represent the first example of metabolic activatio n of a 3-alkyl-7-azaindole nucleus.