Borchardt R T, Reid J R, Thakker D R
J Med Chem. 1976 Oct;19(10):1201-9. doi: 10.1021/jm00232a007.
A series of methylated analogues of 6-hydroxydopamine (6-OHDA) has been synthesized and evaluated as irreversible inhibitors of catechol O-methyltransferase (COMT). These analogues have been prepared in an effort to elucidate the mechanism involved in the inactivation of this enzyme by 6-OHDA. The analogues prepared had methyl groups incorporated in the 2 and/or 5 positions of 6-OHDA so as to block nucleophilic attakc at these positions in the corresponding oxidation products [6-hydroxydopamine-p-quinone (6-OHDAQ), aminochromes I and II]. Such 2- and/or 5-methylated 6-OHDA analogues were found to be inhibitors of COMT with the inactivation apparently resulting from modification of an essential amino acid residue at the active site of the enzyme. The activity of these analogues as inhibitors of COMT argues against a mechanism involving a 1,4 Michael addition reaction by a protein nucleophile at the 2 or 5 positions on 6-OHDAQ or on the corresponding aminochromes. Instead, an alternative mechanism is proposed to explain these data, which involves attack of a protein nucleophile at the carbonyl group in the 6 position of 6-OHDAQ or at the imine functionality on aminochromes I and II. The results of the present experiments have provided insight into the mechanism involved in inactivation of COMT by 6-OHDA. In addition, this study has provided considerable insight into the chemical reactivity of the electrophilic species generated after oxidation of 6-OHDA.
已合成了一系列6-羟基多巴胺（6-OHDA）的甲基化类似物，并将其作为儿茶酚氧位甲基转移酶（COMT）的不可逆抑制剂进行了评估。制备这些类似物是为了阐明6-OHDA使该酶失活所涉及的机制。所制备的类似物在6-OHDA的2位和/或5位引入了甲基，以阻断相应氧化产物[6-羟基多巴胺-p-醌（6-OHDAQ）、氨基色素I和II]中这些位置的亲核攻击。发现这种2-和/或5-甲基化的6-OHDA类似物是COMT的抑制剂，失活显然是由于酶活性位点的一个必需氨基酸残基发生了修饰。这些类似物作为COMT抑制剂的活性与一种机制相悖，该机制涉及蛋白质亲核试剂在6-OHDAQ或相应氨基色素的2位或5位进行1,4迈克尔加成反应。相反，提出了一种替代机制来解释这些数据，该机制涉及蛋白质亲核试剂攻击6-OHDAQ 6位的羰基或氨基色素I和II上的亚胺官能团。本实验结果为6-OHDA使COMT失活所涉及的机制提供了深入了解。此外，这项研究对6-OHDA氧化后产生的亲电物质的化学反应性提供了相当多的见解。
