title: Stereoselective potencies and relative toxicities of γ-coniceine and N-methylconiine enantiomers.
abstract: 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.
authors.affiliation: Poisonous Plant Research Laboratory, Agricultural Research Service, United States Department of Agriculture , 1150 E. 1400 N., Logan, Utah 84341, United States.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Lee
authors.forename: Benedict T
authors.initials: BT
authors.lastname: Green
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Welch
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Jordan
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Kip E
authors.initials: KE
authors.lastname: Panter
authors.forename: David
authors.initials: D
authors.lastname: Hughes
authors.forename: Cheng-Wei Tom
authors.initials: CW
authors.lastname: Chang
authors.forename: James A
authors.initials: JA
authors.lastname: Pfister
authors.forename: Dale R
authors.initials: DR
authors.lastname: Gardner
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D018722:Nicotinic Agonists / Q000737:chemistry / Q000633:toxicity*; D011725:Pyridines / Q000737:chemistry / Q000633:toxicity*; D011978:Receptors, Nicotinic / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C045984:gamma-coniceine