ARS | Publication request: Actions of Piperidine Alkaloid Teratogens at Fetal Nicotinic Acetylcholine Receptors.

Submitted to: Neurotoxicology and Teratology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 24, 2010
Publication Date: February 12, 2010
Repository URL: http://www.pprl.ars.usda.gov
Citation: Green, B.T., Lee, S.T., Panter, K.E., Welch, K.D., Cook, D., Pfister, J.A., Kem, W.R. 2010. Actions of Piperidine Alkaloid Teratogens at Fetal Nicotinic Acetylcholine Receptors. Neurotoxicology and Teratology. 32:383-390. Published online at: http://dx.doi.org/10.1016/j.ntt.2010.01.011

Interpretive Summary: Alkaloids that cause birth defects are found in many species of plants including, poison hemlock, wild tree tobacco, tobacco and lupine. In general, alkaloids from these plants cause contractive skeletal defects in the fetus. A comparison of the alkaloids anabasine, anabaseine, anagyrine, ammodendrine, and coniine in two cell lines with fetal characteristics was made. We determined the potencies and efficacies of the five compounds including their enantiomers. These findings lend support to the hypothesis that the mechanism behind the teratogenic potential of these compounds is the inhibition of fetal movement.

Technical Abstract: Teratogenic alkaloids are found in many species of plants including Conium maculatum L., Nicotiana glauca, Nicotiana tabaccum, and multiple Lupinus spp. Fetal musculoskeletal defects produced by alkaloids from these plants include arthrogyropisis, scoliosis, torticollis, kyposis, lordosis, and cleft palate. A pharmacodynamic comparison of the alkaloids ammodendrine, anabasine, anabaseine, anagyrine, and coniine in SH-SY5Y cells and TE-671 cells was made. These alkaloids and their enantiomers were more effective in depolarizing TE-671 cells which express the human fetal-muscle type nicotinic acetylcholine receptor (nAChR) relative to SH-SY5Y cells which predominately express autonomic nAChRs. The rank order of potency in TE-671 cells was: anabaseine > (+)-anabasine > (-)-anabasine > (±)-anabasine > anagyrine > (-)-coniine > (±)-coniine > (+)-coniine > (±)-ammodendrine > (+)-ammodendrine. The rank order potency in SH-SY5Y cells was: anabaseine > (+)-anabasine > (-)-coniine > (+)-coniine > (+)-ammodendrine > anagyrine > (-)-anabasine > (±)-coniine > (±)-anabasine > (-)-ammodendrine. The actions of these alkaloids at nAChRs in both cell lines could be distinguished by their maximum effects in depolarizing cell membrane potential. The teratogenic action of these compounds may be related to their ability to activate and subsequently desensitize nAChRs.