Abstract
3-{[4-(4-Chlorophenyl)piperazin-1-yl]-methyl}-1H-pyrrolo-2,3-β-pyridine (L-745,870) is a dopamine D4 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.
Footnotes
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Send reprint requests to: Kamlesh P. Vyas, Ph.D., Dept. of Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., WP75A-203, West Point, PA 19486. E-mail: kamlesh_vyas{at}merck.com
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↵1 Current address: Department of Development Pharmacology, Agouron Pharmaceuticals, Inc., San Diego, CA.
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↵2 Current address: Cerep, Inc., 15318 NE 95th St., Redmond, WA.
- Abbreviations used are::
- L-745,870
- 3-{[4-(4-chlorophenyl)piperazin-1-yl]-methyl}-1H-pyrrolo-2,3-β-pyridine
- CID
- collision-induced dissociation
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- TFA
- trifluoroacetic acid
- Received September 27, 1999.
- Accepted February 24, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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