title: Biochemical basis for differences in metabolism-dependent genotoxicity by two diazinylpiperazine-based 5-HT2C receptor agonists.
abstract: The biochemical basis for S9-dependent mutagenic response of the 5-HT(2C) receptor agonist and diazinylpiperazine derivative 1 in the Salmonella Ames assay involves P450-mediated bioactivation to DNA-reactive quinone-methide, aldehyde and nitrone intermediates. Mechanistic information pertaining to the metabolism of 1 was used in the design of diazinylpiperazine 5 to eliminate the safety liability. While 5 was negative in the Ames assay, the compound retained the ability of 1 to form certain electrophilic intermediates. Plausible hypotheses that can collectively account for the differences in mutagenic response of the two piperazine analogs are discussed.
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Bauman
authors.forename: Kim F
authors.initials: KF
authors.lastname: McClure
authors.forename: Jiri
authors.initials: J
authors.lastname: Aubrecht
authors.forename: Santo R
authors.initials: SR
authors.lastname: Cortina
authors.forename: Janvi
authors.initials: J
authors.lastname: Paralkar
mesh_terms: D000577:Amides / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002845:Chromatography / Q000379:methods; D015195:Drug Design; D008956:Models, Chemical; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D009249:NADP / Q000737:chemistry; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D015203:Reproducibility of Results; D012475:Salmonella / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists
chemical_list: D000577:Amides; D009153:Mutagens; D010879:Piperazines; D058826:Serotonin 5-HT2 Receptor Agonists; D000077489:Piperazine; D009249:NADP