Wikström H, Elebring T, Hallnemo G, Andersson B, Svensson K, Carlsson A, Rollema H
Department of Pharmacology, University of Göteborg, Sweden.
J Med Chem. 1988 Jun;31(6):1080-4. doi: 10.1021/jm00401a005.
Aromatic ortho-hydroxylation in the liver might be one of several possible reasons for the low bioavailabilities of the potent, centrally acting dopaminergic and serotoninergic agonists 5- and 8-hydroxy-2-(di-n-propylamino)tetralin, respectively. In vitro and in vivo experiments showed that such an oxidative metabolism did indeed take place. However, the amount of hydroxylated metabolites found in the brain was estimated to represent only 0.3% of the total amount of drug administered. The O-methylation rates of these catechols were also measured in vitro and showed that 5,6-dihydroxy-2-(di-n-propylamino)tetralin is a poor substrate for catechol O-methyltransferase (COMT) and that its 7,8-dihydroxy isomer is virtually devoid of substrate activity. No O-methylated metabolites were detected in the in vivo samples analyzed. A new synthetic strategy was applied to achieve the isomeric catechols studied. 5-Methoxy- or 8-methoxy-2-(di-n-propylamino)tetralin was lithiated in the ortho position and the metalated species was subsequently quenched in nitrobenzene, yielding the methoxy hydroxy isomers, which were heated in 48% aqueous HBr to achieve the corresponding catechols.
肝脏中的芳香邻位羟基化可能是强效的中枢性多巴胺能和5-羟色胺能激动剂5-羟基-2-(二正丙基氨基)四氢萘和8-羟基-2-(二正丙基氨基)四氢萘生物利用度低的几种可能原因之一。体外和体内实验表明这种氧化代谢确实会发生。然而，在脑中发现的羟基化代谢物的量估计仅占给药药物总量的0.3%。还在体外测量了这些儿茶酚的O-甲基化率，结果表明5,6-二羟基-2-(二正丙基氨基)四氢萘是儿茶酚O-甲基转移酶（COMT）的不良底物，其7,8-二羟基异构体实际上没有底物活性。在所分析的体内样品中未检测到O-甲基化代谢物。应用了一种新的合成策略来制备所研究的异构体儿茶酚。5-甲氧基-或8-甲氧基-2-(二正丙基氨基)四氢萘在邻位被锂化，随后金属化物种在硝基苯中淬灭，生成甲氧基羟基异构体，将其在48%的氢溴酸水溶液中加热以得到相应的儿茶酚。
