β受体阻断剂的小肠吸收速率与分子结构的相关性

Correlation between absorption rates of β-adrenoreceptor antagonists in rat small intestine and their molecular structures

目的研究β受体阻断剂在大鼠小肠段的吸收速率常数与分子结构参数的相关性。方法用分子力学MM+法得到β受体阻断剂分子的优化几何构型,用MonteCarlo法计算分子体积,用半经验自洽场分子轨道CNDO/2法计算原子净电荷,相关分析采用逐步多元回归分析法。结果β受体阻断剂在大鼠空肠和大鼠回肠的吸收速率常数与分子中所有氢原子净电荷之和(ΣQH)和分子体积(V)具有很好的线性相关性,ΣQH值和分子体积较小的β受体阻断剂在大鼠空肠和大鼠回肠的吸收速率常数均较大。结论β受体阻断剂在大鼠小肠段的吸收速率常数主要与化合物的脂溶性、形成氢键能力和分子大小有关,脂溶性较大、形成氢键能力较弱和分子体积较小的β受体阻断剂在大鼠小肠段的吸收速率常数较大。

Objective: To study the correlation between the absorption rate constants of β-adrenoreceptor ~antago- ~nists in rat small intestinal segments and their molecular structural parameters.Methods: The net atomic charges and the molecular volumes of 11 β-adrenoreceptor antagonists were obtained with the semiempirical ~self- consistent field molecular orbital calculation CNDO/2 method and Mont Carlo method respectively,using the minimum energy conformation obtained from the optimization of the standard molecular geometry with the molecular mechanics MM+ method.The stepwise multiple regression analysis was used to obtain the correlation equations.Results: The absorption rate constants of β-adrenoreceptor antagonists in rat jejunum or ileum were well linearly correlated with the sum of the net charges of all hydrogen atoms and the molecular volumes.The β-adrenoreceptor antagonist with higher lipophilicity,weaker hydrogen-bonding potential,and smaller molecular volume had greater absorption rate constants.Conclusion: The absorption rate constants of β-adrenoreceptor antagonists in rat small intestinal segments are mainly related with their lipophilicity,hydrogen-bonding potential and molecular size. [