Ziegler R, Ho B, Castagnoli N
J Med Chem. 1981 Oct;24(10):1133-8. doi: 10.1021/jm00142a004.
The popular antihistamine methapyrilene [N,N-dimethyl-N'-(2-pyridyl)-N'-(2-thienylmethyl)-1,2-ethanediamine] recently has been shown to be a potent hepatocarcinogen. Metabolic studies with rabbit liver 100000g microsomal preparations have resulted in the partial characterization of the in vitro metabolic profile of methapyrilene. Evidence for the formation of the N-oxide and the three possible carbinolamines resulting from the NADPH-dependent oxidation of the (dimethylamino)ethyl side chain nitrogen and carbon atoms of methapyrilene is presented. Attempts to trap iminium ion intermediates with electrophilic alkylating potential by coincubating methapyrilene with sodium cyanide have led to the isolation of N-(cyanomethyl)normethapyrilene. The possibility of characterizing the iminium ion intermediate that would result from the oxidative deamination of the dimethylamino moiety was precluded by the chemical instability of the corresponding alpha-cyano amine, which undergoes a spontaneous retro-Michael reaction and hydrolysis to the corresponding amide. The results are discussed in terms of the metabolic activation of methapyrilene to potential alkylating species.
常用抗组胺药甲吡咯烷 [N,N-二甲基-N'-(2-吡啶基)-N'-(2-噻吩基甲基)-1,2-乙二胺] 最近被证明是一种强效肝癌致癌物。对兔肝100000g微粒体制剂进行的代谢研究，已部分表征了甲吡咯烷的体外代谢谱。本文提供了甲吡咯烷的 (二甲基氨基) 乙基侧链氮原子和碳原子经NADPH依赖性氧化形成N-氧化物和三种可能的甲醇胺的证据。通过将甲吡咯烷与氰化钠共同孵育来捕获具有亲电烷基化潜力的亚胺离子中间体的尝试，已导致分离出N-(氰基甲基)去甲甲吡咯烷。由于相应的α-氰基胺化学不稳定，会发生自发的逆迈克尔反应并水解为相应的酰胺，因此无法表征由二甲基氨基部分氧化脱氨产生的亚胺离子中间体。本文根据甲吡咯烷代谢活化为潜在烷基化物种的情况对结果进行了讨论。
