title: Metabolism of A dopamine D(4)-selective antagonist in rat, monkey, and humans: formation of A novel mercapturic acid adduct.
abstract: 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 would not exhibit the extrapyramidal side effects often observed with the use of classical antipsychotic agents. The metabolism of L-745,870 in vivo was investigated in the rat, rhesus monkey, and human using liquid chromatography-tandem mass spectrometry and/or NMR techniques in conjunction with radiochemical 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 latter 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 activation of a 3-alkyl-7-azaindole nucleus.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania and Rahway, New Jersey, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Zhang
authors.forename: P H
authors.initials: PH
authors.lastname: Kari
authors.forename: M R
authors.initials: MR
authors.lastname: Davis
authors.forename: G
authors.initials: G
authors.lastname: Doss
authors.forename: T A
authors.initials: TA
authors.lastname: Baillie
authors.forename: K P
authors.initials: KP
authors.lastname: Vyas
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism / Q000652:urine*; D000818:Animals; D018492:Dopamine Antagonists / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D011758:Pyrroles / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050638:Receptors, Dopamine D4
chemical_list: C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; C493599:DRD4 protein, human; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493601:Drd4 protein, rat; D011725:Pyridines; D011758:Pyrroles; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D000111:Acetylcysteine