CATECHOL O-METHYLTRANSFERASE .2. IN-VITRO INHIBITION BY SUBSTITUTED 8-HYDROXYQUINOLINES
CATECHOL O-METHYLTRANSFERASE .2. IN-VITRO INHIBITION BY SUBSTITUTED 8-HYDROXYQUINOLINES
复制标题
DOI：
10.1021/jm00262a016
复制
发表时间：
1973-01-01
影响因子：
7.3
通讯作者：
BORCHARDT, RT
中科院分区：
文献类型：
--
作者：
BORCHARDT, RT
用邻苯二酚O-甲基转移酶(COMT)将甲基从S-腺苷-L-蛋氨酸转移到邻苯二酚底物上(EC2.1.1.6)在体外被发现被各种取代的8-羟基喹啉类化合物抑制。对一系列取代的8-羟基喹啉类化合物的构效关系进行了研究，并由此进化出了一些迄今报道的最有效的COMT体外抑制剂(如7-碘-8-羟基喹啉-5-磺酸；=8.93×0‘M)。速率研究表明，这些抑制剂对于邻苯二酚底物是线性非竞争性的，对于d‘-腺苷-L-蛋氨酸是非竞争性的；对于镁存在复杂的关系。根据非竞争性速率数据，计算了斜率(AJS)和截距(AJ‘)的抑制常数。测定了这些抑制常数随碱性8-羟基喹啉分子结构变化的变化。对于5-取代化合物，与Hammett a有很好的相关性。8-羟基喹啉对COMT的抑制作用随pH的升高而增强，这可能归因于[i]的降低。AQS在pH为6的范围内保持不变。8-8.3。通过对托洛酮和8-羟基喹啉的联合抑制动力学的研究，得到证据表明，这些抑制剂至少部分结合在去甲肾上腺素的同一部位。去甲肾上腺素的神经元外失活依赖于儿茶酚O-甲基转移酶(COMT)(EC 2.1)。1.6)。H+对儿茶酚胺代谢这一途径的抑制一直是人们感兴趣的研究课题，结果发现了几类合成的2-9和天然的抑制剂。这些抑制剂中的一些已被证明在确定相对免疫水平方面是有用的。
The transfer of a methyl group from S-adenosyl-L-methionine (SAM) to a catechol substrate by the enzyme catechol O-methyltransferase (COMT)(EC 2.1. 1.6) has been found to be inhibited in vitro by various substituted 8-hydroxy quinolines. A study of the structure-activity relationships of a series of substituted 8-hydroxy quinolines was carried out and from this study have evolved some of the most potent in vitroinhibitors of COMT yet reported (eg, 7-iodo-8-hydroxyquinoline-5-sulfonic acid;= 8.93 X\0'M). Rate studies indicate that these inhibitors are linear noncompetitive with respect to catechol substrate and uncompetitive with respect to d'-adenosyl-L-methionine; a complex relationship exists with respect to magnesium. From the noncompetitive rate data were calculated the inhibition constants for the slope (Ajs) and intercept (Aj¡). Variation of these inhibition contants with structural changes on the basic 8-hydroxy quinoline molecule was determined. For 5-substituted compounds a good correlation with Hammett a was observed. The ability of 8-hydroxy quinoline to inhibit COMT was found to increase with increasing pH which could be attributed to a decrease in* i¡. Aqs was found to remain constant over the pH range of6. 8-8.3. By studying the kinetics of inhibition of combinations of tropolone and 8-hydroxy quinoline, evidence was obtained to indicate these inhibitors bind at least partly to the same site on theThe extraneuronal inactivation of norepinephrine is de-pendent upon the enzyme catechol O-methyltransferase (COMT)(EC 2.1. 1.6). h+ The inhibition of this route of catecholamine metabolism has been thesubject of considerable research, interest resulting in the identification of several classes of synthetic2-9 and natural inhibitors. 10 Some of these inhibitors have proven useful in ascertaining the relative im-