Kelley M, Lambert I, Merrill J, Safe S
Biochem Pharmacol. 1985 Oct 1;34(19):3489-94. doi: 10.1016/0006-2952(85)90722-1.
1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) resembles phenobarbital (PB) in its mode of induction of the hepatic drug-metabolizing enzymes in mice. The structural features of this molecule include: a linear tricyclic aromatic ether ring system, an internal 1,4-disubstituted benzene ring and two 3,5-dichloropyridyloxy substituents. Ten analogs of TCPOBOP have been synthesized and their activities as microsomal enzyme inducers evaluated. Dose-response induction of mice hepatic microsomal cytochrome P-450, aldrin epoxidase and dimethylaminoantipyrine N-demethylase gave ED50 values for TCPOBOP and five homologs. The results illustrate that changes in the structure of the pyridyloxy ring markedly affect enzyme induction activity. The order of activity for the substituents was 3,5-dibromopyridyloxy approximately 3,5-dichloropyridyloxy greater than 5-bromopyridyloxy approximately 5-chloropyridyloxy greater than 3-chloropyridyloxy greater than pyridyloxy. In addition, the effects of altered substitution pattern of the benzene ring and structural alterations of the internal ring moiety were evaluated by measuring hepatic microsomal coumarin hydroxylase activity. The results confirm the microsomal monooxygenase enzyme induction activity of TCPOBOP, and the observed structure-dependent potencies of several related homologs support a receptor-mediated mechanism of action for the process.
1,4-双[2-(3,5-二氯吡啶氧基)]苯（TCPOBOP）在诱导小鼠肝脏药物代谢酶的方式上与苯巴比妥（PB）相似。该分子的结构特征包括：一个线性三环芳香醚环系统、一个内部的1,4-二取代苯环和两个3,5-二氯吡啶氧基取代基。已合成了10种TCPOBOP的类似物，并评估了它们作为微粒体酶诱导剂的活性。通过对小鼠肝脏微粒体细胞色素P-450、艾氏剂环氧化酶和二甲基氨基安替比林N-脱甲基酶的剂量反应诱导实验，得出了TCPOBOP及其5种同系物的半数有效剂量（ED50）值。结果表明，吡啶氧基环结构的变化显著影响酶诱导活性。取代基的活性顺序为：3,5-二溴吡啶氧基≈3,5-二氯吡啶氧基＞5-溴吡啶氧基≈5-氯吡啶氧基＞3-氯吡啶氧基＞吡啶氧基。此外，通过测量肝脏微粒体香豆素羟化酶活性，评估了苯环取代模式改变和内环部分结构改变的影响。结果证实了TCPOBOP的微粒体单加氧酶诱导活性，并且观察到的几种相关同系物的结构依赖性效力支持了该过程的受体介导作用机制。
