title: Fetal muscle-type nicotinic acetylcholine receptor activation in TE-671 cells and inhibition of fetal movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine.
abstract: Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock (Conium maculatum L.). Coniine teratogenicity is hypothesized to be attributable to the binding, activation, and prolonged desensitization of fetal muscle-type nAChR, which results in the complete inhibition of fetal movement. However, pharmacological evidence of coniine actions at fetal muscle-type nAChR is lacking. The present study compared (-)-coniine, (+)-coniine, and nicotine for the ability to inhibit fetal movement in a day 40 pregnant goat model and in TE-671 cells that express fetal muscle-type nAChR. Furthermore, α-conotoxins (CTx) EI and GI were used to antagonize the actions of (+)- and (-)-coniine in TE-671 cells. (-)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting fetal movement than was (+)-coniine, suggesting stereoselectivity by the receptor. The pyridine alkaloid nicotine did not inhibit fetal movement in a day 40 pregnant goat model, suggesting agonist specificity for the inhibition of fetal movement. Low concentrations of both CTxs potentiated the TE-671 cell response and higher concentrations of CTx EI, and GI antagonized the actions of both coniine enantiomers demonstrating concentration-dependent coagonism and selective antagonism. These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at fetal muscle-type nAChR in a concentration-dependent manner.
authors.affiliation: Poisonous Plant Research Laboratory, Agricultural Research Service, United States Department of Agriculture, 1150 E. 1400 N. Logan, UT 84321, USA. ben.green@ars.usda.gov
authors.forename: Benedict T
authors.initials: BT
authors.lastname: Green
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Lee
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Welch
authors.forename: James A
authors.initials: JA
authors.lastname: Pfister
authors.forename: Kip E
authors.initials: KE
authors.lastname: Panter
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000470:Alkaloids / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D020916:Conotoxins / Q000494:pharmacology; D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D005260:Female; D005324:Fetal Movement / Q000187:drug effects*; D006041:Goats; D006801:Humans; D008333:Mandelic Acids / Q000737:chemistry; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000196:embryology; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011247:Pregnancy; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D002121:Calcium Channel Blockers; D020916:Conotoxins; D008333:Mandelic Acids; D010880:Piperidines; D011978:Receptors, Nicotinic; C007112:coniine; D000109:Acetylcholine; C037938:mandelic acid