Rekka E, Timmermann H, Bast A
Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Agents Actions. 1989 Apr;27(1-2):184-7. doi: 10.1007/BF02222234.
The aim of this study was to define the structural characteristics in a series of 21 analogues of the anti-histaminergic drug diphenhydramine which are important for the interaction with cytochrome P-450. The compounds gave substrate (type I) binding spectra with rat hepatic microsomal cytochrome P-450. The main findings were: (1) two phenyl rings are needed for strong binding: saturation or elimination of one ring, or restriction of two phenyls with a two-carbon bridge results in a decrease of binding, (2) substitution on one or both aromatic rings has only a small influence on binding, (3) an amine nitrogen contributes to better binding; decrease or absence of basicity weakens binding, and (4) a chain of 4 to 7 atoms connecting the basic centre with the aromatic part is needed; reduction of the chain length, or restriction of it to a cyclic structure causes decrease or loss of binding ability.
本研究的目的是确定抗组胺药苯海拉明的21种类似物的结构特征，这些特征对于与细胞色素P - 450的相互作用很重要。这些化合物与大鼠肝微粒体细胞色素P - 450产生底物（I型）结合光谱。主要发现如下：（1）强烈结合需要两个苯环：一个环的饱和或消除，或用二碳桥限制两个苯环会导致结合力下降；（2）一个或两个芳香环上的取代对结合的影响很小；（3）胺氮有助于更好地结合；碱性降低或不存在会削弱结合；（4）需要一条由4至7个原子组成的链将碱性中心与芳香部分连接起来；链长度的缩短或将其限制为环状结构会导致结合能力下降或丧失。
