QSAR OF NORTROPANE-SUBSTITUTED BENZAMIDES - USE OF LIPOPHILIC (RP-HPLC) AND ELECTRONIC (H-1-NMR) PARAMETERS
QSAR OF NORTROPANE-SUBSTITUTED BENZAMIDES - USE OF LIPOPHILIC (RP-HPLC) AND ELECTRONIC (H-1-NMR) PARAMETERS
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DOI：
10.1016/0223-5234(89)90110-4
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发表时间：
1989-03-01
影响因子：
6.7
通讯作者：
TESTA, B
中科院分区：
文献类型：
--
作者：
COLLIN, S;ELTAYAR, N;TESTA, B
4-benzamido-nortropanes，一个亚组的神经安定药物的药理学和生物化学活性，与实验和计算参数描述的结构特性，如亲脂性或电子分布。亲脂性使用HPLC方法实验测量，并使用疏水II值理论计算。1H NMR化学位移用于描述电子结构。在苯甲酰胺部分5位具有不同取代基的一系列15种托帕必利类似物中，疏水值和抗多巴胺能活性之间存在抛物线关系，表明亲脂性肯定是影响其对D2受体亲和力的主要性质。在一系列的8个3-取代衍生物的亲和力和ammonium氢化学位移之间的线性相关性表明，在某些情况下，苯并ammonium氢键的稳定性可能发挥了主导作用。用从头算方法对一些取代的正构酰胺的电子性质进行了定量计算，以解释3位取代基的间接效应。
The pharmacological and biochemical activities of 4-benzamido-nortropanes, a subgroup of neuroleptic drugs, are correlated with experimental and calculated parameters describing structural properties, such as lipophilicity or electronic distribution. The lipophilicity was experimentally measured using the HPLC method and theoretically calculated using hydrophobic II values. 1H NMR chemical shifts were used to describe the electronic structure. In a series of fifteen tropapride analogues with various substituents at position 5 on the benzamide moiety, a parabolic relationship was obtained between hydrophobic values and anti-dopaminergic activities, indicating that lipophilicity is certainly the major property influencing their affinity for the D2 receptor. The linear correlation between affinities and the amidic hydrogen chemical shifts in a series of eight 3-substituted derivatives shows that the stability of the intrabenzamidic hydrogen bond may play a preponderant role in some cases. The electronic properties of some substituted orthopramides are quantified by ab initio theoretical calculations in order to explain the indirect effect of the substituent at position 3.