Relative toxicities and neuromuscular nicotinic receptor agonistic potencies of anabasine enantiomers and anabaseine
Relative toxicities and neuromuscular nicotinic receptor agonistic potencies of anabasine enantiomers and anabaseine
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DOI：
10.1016/j.ntt.2005.12.010
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发表时间：
2006-03-01
影响因子：
2.9
通讯作者：
Pfister, JA
中科院分区：
文献类型：
--
作者：
Lee, ST;Wildeboer, K;Pfister, JA
野生树烟草（Nicotiana glauca）中的假木贼碱和某些动物毒液中的假木贼碱是烟碱受体激动剂毒素。假木贼碱缺少假木贼碱的亚胺双键;假木贼碱的两种可能的对映体出现在N. glauca。S-和R-假木贼碱的相对效力的比较以前没有报道过。我们通过外消旋N-甲基-N-苯基-N-甲基-N-甲基-N-苯基-N-苯基-N-甲基-N-苯基-N-甲基-N-苯基-N-甲基-N-苯基-N-苯基-N-甲基-N-苯基-N-甲基-N-苯基-N-甲基-N-苯基-N-苯基-N-甲基-N-苯基-N-甲基-N-苯基-N-苯基-N-甲基-N-苯基-N-苯基-N-甲基-N-苯基-N-甲基-N-苯基-N-苯基-N-甲基-N-N-苯基-N-苯基-N-甲基-N-N-苯基-N-甲基-N-N-苯基-N-甲基-N-N-苯基-N-甲基-N-N-苯基-苯基-N-甲基-N-N-苯基-N-甲基-N-N-苯基-甲基-N-N-苯基-N-甲基-N-N-苯基-N-甲基-N-N-苯基-N-甲基-N-N-N- glauca天然产物与9-芴基甲氧羰基-L-丙氨酸（Fmoc-L-Ala-OH）反应，得到非对映异构体，通过制备型反相HPLC分离。然后通过Edman降解获得S-和R-假木贼碱对映异构体级分。使用小鼠生物测定来确定S-和R-富集的假木贼碱对映体的相对致死率。富含（+）-R-假木贼碱的级分的静脉内LD 50为11 +/-1.0 mg/kg，富含（-）-S-假木贼碱的级分的静脉内LD 50为16 +/-1.0 mg/kg。毒扁豆碱的LD_（50）为0.58~0.05 mg/kg。在小鼠生物测定中，假木贼碱的毒性显著高于S-假木贼碱（27倍）和R-假木贼碱（18倍）。这三种生物碱对人胎儿烟碱型神经肌肉受体的相对激动作用大小顺序相同：假木贼碱>> R-假木贼碱> S-假木贼碱。(c)2006年由Elsevier Inc.出版
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. (c) 2006 Published by Elsevier Inc.