The local anesthetic activity of Aconitum alkaloids can be explained by their structural properties:: a QSAR analysis
The local anesthetic activity of Aconitum alkaloids can be explained by their structural properties:: a QSAR analysis
复制标题
DOI：
10.1111/j.1472-8206.2004.00222.x
复制
发表时间：
2004-04-01
影响因子：
2.9
通讯作者：
Nava-Ocampo, AA
中科院分区：
文献类型：
--
作者：
Bello-Ramírez, AM;Nava-Ocampo, AA
从黄芪中分离出的生物碱对周围神经有麻醉作用。本文对11个生物碱类化合物进行了定量构效关系（QSAR）分析，以了解其作为局麻药的作用机制。具有最高麻醉活性的生物碱在R-14位具有芳酰基/芳酰氧基，而较弱麻醉活性的生物碱在R-4位具有芳酰氧基。稳定的化合物比不稳定的化合物表现出更高的局部麻醉活性。从芳香环上原子的反应活性指数来看，麻醉活性最高的化合物中，C2'的反应活性较高，C3'和C5'的反应活性较低。两组生物碱的N、C1 '、C4'和C6'的反应性相似。两组的pK（a）均约为7.3。生物碱的局部麻醉ED_（50）与分子量、核-核排斥能、空间位阻能和RI-C_（2 '）呈显著负相关，与电子能、总能量、RI-C_（5'）和生成热呈显著正相关。总之，我们确定了一组结构参数，与局部麻醉活性的生物碱。我们的研究结果是有用的，以了解这些生物碱的作用机制，并提供了一个合理的化学操作的化合物，以获得有效的衍生物与轻微的毒性。
Alkaloids isolated from Aconitum roots exhibit anesthetic effects at peripheral nerves. We performed the present quantitative structure-activity relationship (QSAR) analysis in order to understand the mechanism of action as local anesthetics of 11 Aconitum alkaloids. The alkaloids with the highest anesthetic activity had an aroyl/ aroyloxy group at R-14 position while the weaker anesthetic alkaloids had the aroyloxy group at R-4. The stable compounds exhibited a higher local anesthetic activity than the unstable compounds. In relation to the reactivity indexes of atoms on the aromatic ring, C2' was more reactive while C3' and C5' were less reactive in the compounds with the highest anesthetic activity. Reactivity of N, C1', C4' and C6' was similar between the two groups of alkaloids. The pK(a) was approximately 7.3 in both groups. The local anesthetic ED50 of alkaloids was significantly inversely related to molecular weight, core-core repulsion energy, steric energy and RI-C2', and directly related to electronic energy, total energy, RI-C5' and to the heat of formation. In conclusion, we identified a set of structural parameters that are related to the local anesthetic activity of Aconitum alkaloids. Our findings are useful to understand the mechanism of action of these alkaloids and to provide a rational for chemical manipulation of the compounds in order to obtain potent derivates with minor toxicity.