Stereoselective Potencies and Relative Toxicities of γ-Coniceine and N-Methylconiine Enantiomers
Chemical Research in Toxicology
American Chemical Society
γ-Coniceine, coniine, and N-methylconiine are toxic alkaloids present in poison hemlock (Conium maculatum). We previously reported the comparison of the relative potencies of (+)- and (-)-coniine enantiomers. In this study, we synthesized γ-coniceine and the enantiomers of N-methylconiine and determined the biological activity of γ-coniceine and each of the N-methylconiine enantiomers in vitro and in vivo. The relative potencies of these piperidine alkaloids on cells expressing human fetal muscle-type nicotinic acetylcholine receptors had the rank order of γ-coniceine > (−)-N-methylconiine > (±)-N-methylconiine > (+)-N-methylconiine. The relative lethalities of γ-coniceine and (−)-, (±)-, and (+)-N-methylconiine in vivo using a mouse bioassay were 4.4, 16.1, 17.8, and 19.2 mg/kg, respectively. The results from this study suggest γ-coniceine is a more potent agonist than the enantiomers of N-methylconiine and that there is a stereoselective difference in the in vitro potencies of the enantiomers of N-methylconiine that correlates with the relative toxicities of the enantiomers in vivo.
Lee, S. T.; Green, B. T.; Welch, K. D.; Jordan, G. T.; Zhang, Q.; Panter, K. E.; Hughes, D.; Chang, C.-W. T.; Pfister, J. A.; Gardner, D. R. "Stereoselective Potencies and Relative Toxicities of γ-Coniceine and N-Methylconiine Enantiomers." Chem. Res. Toxicol. 2013, 26, 616−621. PubMed PMID: 23514442.