COMPARATIVE-ANALYSIS OF THE EFFECTS OF SYNTHETIC DERIVATIVES OF BATRACHOTOXIN ON SODIUM CURRENTS IN FROG NODE OF RANVIER
COMPARATIVE-ANALYSIS OF THE EFFECTS OF SYNTHETIC DERIVATIVES OF BATRACHOTOXIN ON SODIUM CURRENTS IN FROG NODE OF RANVIER
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DOI：
10.1007/bf00711639
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发表时间：
1992-02-01
影响因子：
4
通讯作者：
LEONOV, VN
中科院分区：
文献类型：
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作者：
KHODOROV, BI;YELIN, EA;LEONOV, VN
1.在有髓神经纤维的电压钳实验中，观察了从7，8-二氢巴曲霉毒素A(DBTX-A)合成的9个巴曲霉毒素(BTX)衍生物对Na+电流(I(Na))的影响。DBTX-A与2，4，5-三甲基吡咯-3-羧酸(DBTX-P)和苯甲酸(DBTX)在10(-5)M浓度时对I(Na)的修饰作用与BTX2，4，5-三甲基吡咯-3-羧酸(DBTX-P)和苯甲酸(DBTX)引起的I(Na)修饰性质相似。DBTX的四元衍生物(QDBTX)仅在5.10(-4)M的浓度下才产生这种I(Na)的变化，显然是由于其低得多的脂溶性所致。三级氮原子附近同型吗啉环上的a-CH2-被a-C=O基团取代后，DBTX活性被取消，这强烈地表明了三级氮质子化对毒素与通道受体相互作用的必要性。将DBTX分子中的11-羟基从α位置转移到β位置并没有降低其活性，尽管在β位置这个基团在空间上是非常受阻的。11-β-DBTX的活性与Codding(1983)的“氧三联体”假说的预测不一致。DBTX-A和从DBTX通过氧化11α-羟基(K-DBTX)、乙酰化(Ac-DBTX)或还原半缩酮(H_2DBTX)得到的化合物，即使在10(-3)M的浓度下也只能修饰很小部分的Na通道。然而，在正常和修饰的钠通道上都观察到明显的可逆阻断作用。这些结果使我们得出结论，BTX只以带电的形式修饰钠通道，半缩酮和20-α-酯部分提供了足够的毒素在受体表面的处置。H_2DBTX、DBTX-A、K-DBTX和Ac-DBTX不能修饰大多数钠通道的原因可以解释为这些配体在受体表面的“正确配置概率”很低。
1. 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 (I(Na)) 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 I(Na) qualitatively similar to that induced by BTX.3. The quaternary derivative of DBTX (QDBTX) produced such changes in I(Na) 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.