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Piperidine, pyridine alkaloid inhibition of fetal movement in a day 40 pregnant goat model

Benedict T. Green, Stephen T. Lee, Kevin D. Welch, James A. Pfister, Kip E. Panter
Food and chemical toxicology 2013 v.58 pp. 8-13
agonists, anabasine, conotoxins, fetal development, fetus, goats, membrane potential, models, nicotinic receptors, piperidines, toxicology
Inhibition of fetal movement is one mechanism behind the development of multiple congenital contracture-type defects in developing fetuses of humans and animals. We tested the alkaloids anabasine, lobeline, and myosmine for agonist actions, and sensitivity to alpha conotoxins EI and GI blockade at fetal muscle-type nicotinic acetylcholine receptors (nAChR) expressed by TE-671 cells. We also determined if the alkaloids decreased fetal movement in an IV dosed, day 40 pregnant goat model. In TE-671 cells, all three alkaloids elicited concentration-dependent changes in membrane potential sensing dye fluorescence. 1.0μM alpha conotoxin GI shifted the concentration–effect curves of anabasine and myosmine to the right, and decreased maximal responses. Neither of the conotoxins blocked the actions of lobeline in TE-671 cells. In the day 40 pregnant goats, 0.8mg/kg anabasine abolished fetal movement at 30 and 60min after dosing and fetal movement was reduced by lobeline and myosmine. The blockade of anabasine and myosmine actions in TE-671 cells by alpha conotoxin GI indicates that they are agonists at fetal muscle-type nAChR. All three alkaloids did significantly decrease fetal movement in the day 40 pregnant goat model suggesting a potential for these alkaloids to cause multiple congenital contracture-type defects in developing fetuses.