Wins Pierre, Margineanu Ilca, Penelle Jacques, Angenot Luc, Grisar Thierry, Bettendorff Lucien
Center for Cellular and Molecular Neurobiology, University of Liège, place Delcour, 17, 4020 Liège, Belgium.
Naunyn Schmiedebergs Arch Pharmacol. 2003 Mar;367(3):253-9. doi: 10.1007/s00210-003-0692-9. Epub 2003 Feb 19.
Several mono- and bisindole quaternary alkaloids isolated from the stem bark of Strychnos guianensis have recently been shown to be effective blockers of neuromuscular transmission in mice. In this study, we used a human clonal cell line (TE671) expressing muscle-type nicotinic acetylcholine receptors. The agonist carbamylcholine activated a receptor-mediated (86)Rb(+) efflux and this activation was antagonized by the indole alkaloids, the most active being bisindole bisquaternary compounds. The most effective antagonist, guiachrysine, had an IC(50) around 0.43 microM in the presence of 0.5 mM carbamylcholine, compared to 0.16 microM for d-tubocurarine, the most potent curarizing alkaloid. Guiaflavine and 5',6'-dehydroguiaflavine were slightly less effective. Monoindole compounds were 10 to 100 times less potent than bisindole alkaloids. Kinetic analysis showed that the inhibition of the carbamylcholine-dependent (86)Rb(+) efflux by guiaflavine was of mixed competitive and uncompetitive type. The competitive component (K(I)=0.21 microM) is presumably due to binding at the acetylcholine site, while the uncompetitive component (K'(I)=0.92 microM) may be due to open channel block.
最近从圭亚那马钱子茎皮中分离出的几种单吲哚和双吲哚季铵生物碱已被证明是小鼠神经肌肉传递的有效阻滞剂。在本研究中，我们使用了表达肌肉型烟碱乙酰胆碱受体的人克隆细胞系（TE671）。激动剂氨甲酰胆碱激活了受体介导的（86）Rb（+）外流，这种激活被吲哚生物碱拮抗，其中最具活性的是双吲哚双季铵化合物。最有效的拮抗剂桂雅辛在存在0.5 mM氨甲酰胆碱的情况下IC（50）约为0.43 microM，而最有效的箭毒样生物碱d -筒箭毒碱的IC（50）为0.16 microM。桂黄酮和5'，6'-脱氢桂黄酮的效果稍差。单吲哚化合物的效力比双吲哚生物碱低10至100倍。动力学分析表明，桂黄酮对氨甲酰胆碱依赖性（86）Rb（+）外流的抑制作用是混合竞争和非竞争类型。竞争成分（K（I）=0.21 microM）可能是由于在乙酰胆碱位点的结合，而非竞争成分（K'（I）=0.92 microM）可能是由于开放通道阻滞。
