| 19246199 |
Kalgutkar AS, Bauman JN, McClure KF, Aubrecht J, Cortina SR, Paralkar J: Biochemical basis for differences in metabolism-dependent genotoxicity by two diazinylpiperazine-based 5-HT2C receptor agonists. Bioorg Med Chem Lett. 2009 Mar 15;19(6):1559-63. Epub 2009 Feb 12.
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. |
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