Gessner W, Brossi A, Shen R, Abell C W
J Med Chem. 1985 Mar;28(3):311-7. doi: 10.1021/jm00381a009.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a nigrostriatal neurotoxin which can cause irreversible parkinsonism in humans and primates by selective destruction of neurons in the substantia nigra. It is possible that MPTP could be metabolized by hydroxylation of the phenyl ring and/or aromatization of its nitrogen-containing ring. Hydroxylated derivatives of 4-phenyl-1,2,3,6-tetrahydropyridine, 4-phenylpiperidine, and 4-phenylpyridine were synthesized and tested in vitro as inhibitors of dihydropteridine reductase (DHPR) from human liver and rat striatal synaptosomes. It was found that all hydroxy derivatives were about 100-10 000 times more inhibitory than MPTP to DHPR. The inhibitory potency of the hydroxylated derivatives increased with the number of hydroxyl substitutions present on the phenyl ring (catechol greater than phenol) and with oxidation of the nitrogen-containing ring (pyridine greater than tetrahydropyridine greater than piperidine).
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）是一种黑质纹状体神经毒素，通过选择性破坏黑质中的神经元，可在人类和灵长类动物中引发不可逆的帕金森症。MPTP有可能通过苯环羟基化和/或其含氮环芳构化进行代谢。合成了4-苯基-1,2,3,6-四氢吡啶、4-苯基哌啶和4-苯基吡啶的羟基化衍生物，并在体外作为人肝脏和大鼠纹状体突触体中二氢蝶啶还原酶（DHPR）的抑制剂进行测试。结果发现，所有羟基化衍生物对DHPR的抑制作用比MPTP强约100 - 10000倍。羟基化衍生物的抑制效力随着苯环上羟基取代数量的增加（儿茶酚大于苯酚）以及含氮环的氧化程度增加（吡啶大于四氢吡啶大于哌啶）而增强。
