蟾毒素合成衍生物对蛙类郎飞结钠电流影响的比较分析。

Comparative analysis of the effects of synthetic derivatives of batrachotoxin on sodium currents in frog node of Ranvier.

作者信息

Khodorov B I, Yelin E A, Zaborovskaya L D, Maksudov M Z, Tikhomirova O B, Leonov V N

机构信息

Institute of General Pathology and Pathological Physiology, USSR Academy of Medical Sciences, Moscow.

出版信息

Cell Mol Neurobiol. 1992 Feb;12(1):59-81. doi: 10.1007/BF00711639.

DOI:10.1007/BF00711639

PMID:1315217

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11567179/

Abstract

In voltage-clamp experiments on frog myelinated nerve fibers, the effects of nine synthetic derivatives of batrachotoxin (BTX) obtained from 7,8-dihydrobatrachotoxinin A (DBTX-A) on Na+ currents (INa) have been investigated. 2. Both of 20 alpha-esters of DBTX-A with 2,4,5-trimethylpyrrol-3-carboxylic acid (DBTX-P) and benzoic acid (DBTX) at a 10(-5) M concentration caused modification of INa qualitatively similar to that induced by BTX. 3. The quaternary derivative of DBTX (QDBTX) produced such changes in INa only at a 5.10(-4) M concentration, apparently due to its much lower lipid solubility. 4. Replacement of a -CH2- by a -C = O. group in the homomorpholine ring near the tertiary nitrogen atom abolished the DBTX activity, strongly suggesting the necessity of tertiary nitrogen protonation for the toxin interaction with the channel receptor. 5. Transfer of an 11-hydroxygroup from the alpha- to the beta-position in the DBTX molecule did not decrease its activity in spite of the fact that in the beta-position this group is sterically very hindered. The activity of 11 beta-DBTX is at variance with the prediction of Codding's (1983) "oxygen triad" hypothesis. 6. DBTX-A and compounds obtained from DBTX by oxidation of the 11 alpha-hydroxygroup (K-DBTX), acetylation (Ac-DBTX), or reduction of the hemiketal moiety (H2DBTX) even at a concentration as high as 10(-3) M were able to modify only a very small fraction of the Na channels. However, a clear-cut reversible blocking action on both normal and modified Na channels was observed. 7. These results led us to conclude that BTX modifies the Na channels only in the charged form and hemiketal and 20 alpha-ester moieties provide adequate disposition of toxin on the receptor surface. The inability of H2DBTX, DBTX-A, and K-DBTX and Ac-DBTX to modify most of the Na channels can be explained by a low "probability of correct disposition" of these ligands on the receptor surface.

摘要

在对青蛙有髓神经纤维进行的电压钳实验中，研究了从7,8 - 二氢蟾毒素A（DBTX - A）获得的九种蟾毒素（BTX）合成衍生物对钠离子电流（INa）的影响。2. DBTX - A与2,4,5 - 三甲基吡咯 - 3 - 羧酸（DBTX - P）和苯甲酸（DBTX）形成的20种α - 酯，在浓度为10^(-5) M时，都会引起INa的变化，其性质与BTX诱导的变化相似。3. DBTX的季铵衍生物（QDBTX）仅在浓度为5×10^(-4) M时才会引起INa的这种变化，显然是由于其脂溶性低得多。4. 在叔氮原子附近的高哌嗪环中，用 -C = O. 基团取代 -CH2 - 基团消除了DBTX的活性，强烈表明叔氮质子化对于毒素与通道受体相互作用是必要的。5. 尽管在β - 位该基团在空间上受到很大阻碍，但将DBTX分子中的11 - 羟基从α - 位转移到β - 位并没有降低其活性。11β - DBTX的活性与科丁（1983年）“氧三联体”假说的预测不一致。6. DBTX - A以及通过氧化11α - 羟基（K - DBTX）、乙酰化（Ac - DBTX）或还原半缩酮部分（H2DBTX）从DBTX获得的化合物，即使在高达10^(-3) M的浓度下，也只能改变极小部分的钠通道。然而，观察到对正常和修饰的钠通道都有明显的可逆阻断作用。7. 这些结果使我们得出结论，BTX仅以带电形式修饰钠通道，半缩酮和20α - 酯部分为毒素在受体表面提供了适当的布局。H2DBTX、DBTX - A、K - DBTX和Ac - DBTX无法修饰大多数钠通道，可以用这些配体在受体表面的“正确布局概率”低来解释。