Running title: Optical isomers of coniine inhibit fetal movement (original) (raw)
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Comparison of nicotinic receptor binding and biotransformation of coniine in the rat and chick
1996
Coniine, an alkaloid from Conium maculatum (poison hemlock), is a known teratogen in many domestic species with maternal ingestion resulting in arthrogryposis of the offspring. We have previously shown that rats are not susceptible and rabbits only weakly susceptible to coniine-induced arthrogryposis. However, the chick embryo does provide a reproducible laboratory animal model of coniine-induced teratogenesis. The reason for this cross-species variation is unknown. The purpose of this study was to evaluate coniine binding to nicotinic receptors and to measure coniine metabolism in vitro between susceptible and non-susceptible species. Using the chick model, neither the peripheral nicotinic receptor antagonist d-tubocurarine chloride nor the central nicotinic receptor antagonist trimethaphan camsylate blocked the teratogenesis or lethality of 1.5% coniine (50/zl/egg). Trimethaphan camsylate enhanced coniine-induced lethality in a dose-dependent manner. Neither nicotinic receptor blocker prevented nicotine sulfate-induced malformations but d-tubocurarine chloride did block lethality in a dose-dependent manner. Competition by coniine for [~25I]-~-bungarotoxin to nicotinic receptors isolated from adult rat diaphragm and chick thigh muscle and competition by coniine for [3H]-cytisine to receptors from rat and chick brain were used to assess coniine binding to nicotinic receptors. The ICs0 for coniine in rat diaphragm was 314/tM while that for chick leg muscle was 70 pM. For neuronal nicotinic receptors, the ICsos of coniine for maternal rat brain, fetal rat brain, and chick brain
Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptors
Neurotoxicology and Teratology, 2010
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.
Antinociceptive activity of coniine in mice
Journal of Ethnopharmacology, 2009
Ethnopharmacological relevance: Hemlock was used as an analgesic in certain ethnopharmacological traditions and there has been no record about the antinociceptive effect of coniine which is the major alkaloid compound of Hemlock. Aim of this study: The present study was undertaken to evaluate the possible antinociceptive activity of coniine. Material and methods: Antinociceptive activity of coniine was tested dose in Hotplate test (thermal pain model) and in Writhing test (chemical pain model) in different nociception models. Results: Coniine caused a prolongation in reaction time in Hotplate test at 20 mg/kg dose. In addition, it was observed that coniine decreased the number of writhes in Writhing test. Both data indicated an antinociceptive effect of coniine. A rotarod test was also conducted in order to clarify, whether this activity was related with a loss of locomotion or with an analgesic activity. None of the chemical agents at those doses used in experiments caused a loss of locomotor activity. It was also shown that antinociceptive effect of morphine was potentialized by coniine which was inhibited by nicotinic receptor blocker mecamylamine (1 mg/kg). Conclusion: Coniine has antinociceptive effect via the nicotinic receptors. A pharmacological assessment about the painless death of Socrates due to Hemlock (coniine) toxicity has also been presented by using this data.
Birth Defects Research Part C: Embryo Today: Reviews, 2013
The exposure of a developing embryo or fetus to alkaloids from plants, plant products, or plant extracts has the potential to cause developmental defects in humans and animals. These defects may have multiple causes, but those induced by piperidine and quinolizidine alkaloids arise from the inhibition of fetal movement and are generally referred to as multiple congenital contracture-type deformities. These skeletal deformities include arthrogyrposis, kyposis, lordosis, scoliosis, and torticollis, associated secondary defects, and cleft palate. Structure-function studies have shown that plant alkaloids with a piperidine ring and a minimum of a three-carbon side-chain a to the piperidine nitrogen are teratogenic. Further studies determined that an unsaturation in the piperidine ring, as occurs in gamma coniceine, or anabaseine, enhances the toxic and teratogenic activity, whereas the N-methyl derivatives are less potent. Enantiomers of the piperidine teratogens, coniine, ammodendrine, and anabasine, also exhibit differences in biological activity, as shown in cell culture studies, suggesting variability in the activity due to the optical rotation at the chiral center of these stereoisomers. In this article, we review the molecular mechanism at the nicotinic pharmacophore and biological activities, as it is currently understood, of a group of piperidine and quinolizidine alkaloid teratogens that impart a series of flexuretype skeletal defects and cleft palate in animals. Birth Defects Research (Part C) 99:235-246, View this article online at (wileyonlinelibrary.com).
Stereoselective Potencies and Relative Toxicities of Coniine Enantiomers
Chemical Research in Toxicology, 2008
Coniine, one of the major toxic alkaloids present in poison hemlock (Conium maculatum), occurs in two optically active forms. A comparison of the relative potencies of (+)-and (-)-coniine enantiomers has not been previously reported. In this study, we separated the enantiomers of coniine and determined the biological activity of each enantiomer in Vitro and in ViVo. The relative potencies of these enantiomers on TE-671 cells expressing human fetal nicotinic neuromuscular receptors had the rank order of (-)coniine > (()-coniine > (+)-coniine. A mouse bioassay was used to determine the relative lethalities of (-)-, (()-, and (+)-coniine in ViVo. The LD 50 values of the coniine enantiomers were 7.0, 7.7, and 12.1 mg/kg for the (-)-, (()-, and (+)-forms of coniine, respectively. The results from this study demonstrate that there is a stereoselective difference in the in Vitro potencies of the enantiomers of coniine that directly correlates with the relative toxicities of the enantiomers in ViVo.
General Pharmacology: The Vascular System, 1991
The effects of N-methyl-and N-isobutyl-l,2-diphenyl ethanol amine (compounds M & E), respectively and diltiazem (D) were examined on the spontaneous and evoked uterine contractions of pregnant rats in vitro. 2. Addition of compound M (75-300/zM), compound E (15-60 #M) or D (100-400 nM) to the uterine tissues, inhibited the spontaneous contractions in a dose-dependent manner. The potency order was D>E>M. 3. The inhibitions were reversed by elevating the extracellular Ca 2÷ concentration by 20mM. The compounds also antagonised CaCl~-evoked contractions. 4. Treatment of rats with either compound during pregnancy days (1-I 6) did not affect the implantation process and did not induce any teratogenicity. 5. The uterine inhibitory effects of the compounds may be due to blockade of uterine Ca 2÷ channels.
Toxins, 2016
Teratogenic alkaloids can cause developmental defects due to the inhibition of fetal movement that results from desensitization of fetal muscle-type nicotinic acetylcholine receptors (nAChRs). We investigated the ability of two known teratogens, the piperidinyl-pyridine anabasine and its 1,2-dehydropiperidinyl analog anabaseine, to activate and desensitize peripheral nAChRs expressed in TE-671 and SH-SY5Y cells. Activation-concentration response curves for each alkaloid were obtained in the same multi-well plate. To measure rapid desensitization, cells were first exposed to five potentially-desensitizing concentrations of each alkaloid in log10 molar increments from 10 nM to 100 µM and then to a fixed concentration of acetylcholine (ACh), which alone produces near-maximal activation. The fifty percent desensitization concentration (DC50) was calculated from the alkaloid concentration-ACh response curve. Agonist fast desensitization potency was predicted by the agonist potency measur...