Biochemical basis for differences in metabolism-dependent genotoxicity by two diazinylpiperazine-based 5-HT2C receptor agonists.
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.
Kalgutkar
Amit S
AS
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Bauman
Jonathan N
JN
McClure
Kim F
KF
Aubrecht
Jiri
J
Cortina
Santo R
SR
Paralkar
Janvi
J
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
D000577:Amides; D009153:Mutagens; D010879:Piperazines; D058826:Serotonin 5-HT2 Receptor Agonists; D000077489:Piperazine; D009249:NADP