Nagasawa H T, Elberling J A, DeMaster E G
J Med Chem. 1984 Oct;27(10):1335-9. doi: 10.1021/jm00376a019.
A series of compounds structurally related to pargyline (N-methyl-N-propargylbenzylamine, 4) were synthesized with the propargyl group replaced by a cyclopropyl, allyl, or 2,2,2-trichloroethyl group and, additionally in several cases, with the methyl group replaced by H. The rationale for their preparation was based on the expectation that, like pargyline, which gives rise to propiolaldehyde, oxidative metabolism of the above compounds by the hepatic cytochrome P-450 enzymes would lead to the generation in vivo of the aldehyde dehydrogenase (AlDH) inhibitors, cyclopropanone, acrolein, or chloral. These compounds were evaluated for inhibition of liver AlDH in vivo by measuring the elevation of ethanol-derived blood acetaldehyde in rats and in vitro by the rate of oxidation of acetaldehyde by intact and osmotically disrupted liver mitochondria. Administration of N-methyl-N-cyclopropylbenzylamine (5) and its nor-methyl analogue (8) to rats raised blood acetaldehyde levels significantly over controls at 2 h. This effect was more pronounced at 9 h, with blood acetaldehyde levels reaching 19 to 27 times control values and approaching the values induced by pargyline. Other compounds elicited significant elevations in ethanol-derived blood acetaldehyde only at 9 h. We suggest that latent inhibitors of AlDH such as 5 or 8 might be useful as alcohol deterrent agents.
合成了一系列与帕吉林（N-甲基-N-炔丙基苄胺，4）结构相关的化合物，其中炔丙基被环丙基、烯丙基或2,2,2-三氯乙基取代，并且在几种情况下，甲基被氢取代。制备这些化合物的基本原理是基于这样的预期，即与能产生丙炔醛的帕吉林一样，上述化合物经肝细胞色素P-450酶的氧化代谢会在体内产生醛脱氢酶（AlDH）抑制剂环丙酮、丙烯醛或三氯乙醛。通过测量大鼠体内乙醇衍生的血液乙醛升高情况，以及通过完整的和经渗透破坏的肝线粒体对乙醛的氧化速率，在体内和体外对这些化合物抑制肝脏AlDH的能力进行了评估。给大鼠施用N-甲基-N-环丙基苄胺（5）及其去甲基类似物（8）后，在2小时时血液乙醛水平比对照组显著升高。这种效应在9小时时更为明显，血液乙醛水平达到对照值的19至27倍，接近帕吉林诱导的值。其他化合物仅在9小时时引起乙醇衍生的血液乙醛显著升高。我们认为，像5或8这样的潜在AlDH抑制剂可能用作戒酒剂。
