Relative toxicities and neuromuscular nicotinic receptor agonistic potencies of anabasine enantiomers and anabaseine

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• 作者：Stephen T. Lee ; Kristin Wildeboer ; Kip E. Panter ; William R. Kem ; Dale R. Gardner ; Russell J. Molyneux ; Cheng-Wei Tom Chang ; Ferenc Soti and James A. Pfister
• 关键词：Anabasine ; Anabaseine ; Enantiomer ; Nicotinic receptor ; Toxicity
• 刊名：Neurotoxicology and Teratology
• 出版年：2006
• 出版时间：March-April 2006
• 年：2006
• 卷：28
• 期：2
• 页码：220-228
• 全文大小：226 K

文摘

Anabasine occurring in wild tree tobacco (Nicotiana glauca) and anabaseine occurring in certain animal venoms are nicotinic receptor agonist toxins. Anabasine lacks the imine double bond of anabaseine; the two possible enantiomers of anabasine occur in N. glauca. A comparision of the relative potencies of S- and R-anabasine has not been previously reported. We separated the enantiomers of anabasine by reaction of the racemic N. glauca natural product with 9-fluorenylmethoxycarbonyl-l-alanine (Fmoc-l-Ala-OH) to give diastereomers, which were separated by preparative reversed phase HPLC. The S- and R-anabasine enantiomer fractions were then obtained by Edman degradation. A mouse bioassay was used to determine the relative lethalities of S- and R-enriched anabasine enantiomers. The intravenous LD₅₀ of the (+)-R-anabasine rich fraction was 11 ± 1.0 mg/kg and that of the (−)-S-anabasine-rich fraction was 16 ± 1.0 mg/kg. The LD₅₀ of anabaseine was 0.58 ± 0.05 mg/kg. Anabaseine was significantly more toxic in the mouse bioassay than S-anabasine (27-fold) and R-anabasine (18-fold). The relative agonistic potencies of these three alkaloids on human fetal nicotinic neuromuscular receptors were of the same rank order: anabaseine R-anabasine > S-anabasine.