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-HT2C 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.

A chemical strategy to abolish S9/NADPH-dependent mutagenicity of the 5-HT2C receptor agonist 1 is examined.Figure optionsDownload as PowerPoint slide