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: K E Zhang, P H Kari, M R Davis, G Doss, T A Baillie, K P Vyas
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 28 Issue 6 Pg. 633-42 (Jun 2000) ISSN: 0090-9556 [Print] United States
• PMID: 10820134 (Publication Type: Journal Article)

Chemical References

• 3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine
• DRD4 protein, human
• Dopamine Antagonists
• Dopamine D2 Receptor Antagonists
• Drd4 protein, rat
• Pyridines
• Pyrroles
• Receptors, Dopamine D2
• Receptors, Dopamine D4
• Acetylcysteine

Topics

• Acetylcysteine (metabolism, urine)
• Animals
• Dopamine Antagonists (metabolism, pharmacology, urine)
• Dopamine D2 Receptor Antagonists
• Humans
• Macaca mulatta
• Male
• Pyridines (metabolism, pharmacology, urine)
• Pyrroles (metabolism, pharmacology, urine)
• Rats
• Rats, Sprague-Dawley
• Receptors, Dopamine D2 (metabolism)
• Receptors, Dopamine D4