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Stereoselective potencies and relative toxicities of y-Coniceine and N-Methylconiine enantiomers

Stephen T. Lee, Benedict T. Green, Kevin D. Welch, Kip E. Panter, James A. Pfister, Dale R. Gardner, Glenn T. Jordan, David Hughes, Cheng-Wei Tom Chang, Qian Zhang
Chemical Research in Toxicology 2013 v.26 no.4 pp. 616-621
0893-228X; 1520-5010
Conium maculatum, agonists, animal models, bioassays, enantiomers, human cell lines, in vitro culture, mice, nicotinic receptors, piperidine alkaloids, poisonous plants, stereoselectivity, structure-activity relationships, toxicity, toxicity testing
y-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 '-coniceine and the enantiomers of N-methylconiine and determined the biological activity of '-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 '-coniceine > (-)-N-methylconiine > (')-N-methylconiine > (+)-N-methylconiine. The relative lethalities of '-coniceine, (-)-, (')- 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 '-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.