Wall G M, Baker J K
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University 38677.
J Med Chem. 1989 Jun;32(6):1340-8. doi: 10.1021/jm00126a033.
By use of rat liver or brain homogenate supernatants containing microsomes and/or mitochondria, it was found that the prototype GABAergic prodrug [3-(p-chlorophenyl)pyrrolidine (1)] underwent a series of alpha-oxidation transformations to a pair of amino acid metabolites and a pair of lactam metabolites [4-amino-3-(p-chlorophenyl)butanoic acid, baclofen (5); 4-amino-2-(p-chlorophenyl)butanoic acid (10); 4-(chlorophenyl)pyrrolidin-2-one and 3-(p-chlorophenyl)pyrrolidine-2-one (11)]. With the liver homogenates, the formation of the lactam metabolites was approximately 2 orders of magnitude greater than that of the amino acid metabolites, while with the brain homogenates, the amino acid and lactam pathways were of similar magnitude. For either tissue, for both the lactam and the amino acid series, attack at the less sterically hindered 5-position of the pyrrolidine ring was greater than the attack at the 2-position (5 greater than 10 and 6 greater than 11) with the exception of the liver homogenate mitochondrial fraction (6 less than 11). The parenteral administration of the prodrug 1 was found to give detectable brain levels of 5 as well as activity in an isoniazid-induced (GABA-inhibited) convulsion model.
通过使用含有微粒体和/或线粒体的大鼠肝脏或脑匀浆上清液，发现原型GABA能前药[3-(对氯苯基)吡咯烷(1)]经历了一系列α-氧化转化，生成一对氨基酸代谢物和一对内酰胺代谢物[4-氨基-3-(对氯苯基)丁酸、巴氯芬(5)；4-氨基-2-(对氯苯基)丁酸(10)；4-(氯苯基)吡咯烷-2-酮和3-(对氯苯基)吡咯烷-2-酮(11)]。在肝脏匀浆中，内酰胺代谢物的生成量比氨基酸代谢物大约高2个数量级，而在脑匀浆中，氨基酸和内酰胺途径的生成量相似。对于任一组织，无论是内酰胺系列还是氨基酸系列，除肝脏匀浆线粒体部分外(6小于11)，吡咯烷环空间位阻较小的5-位的反应程度大于2-位的反应程度(5大于10且6大于11)。发现前药1的肠胃外给药在异烟肼诱导的(γ-氨基丁酸抑制的)惊厥模型中可使脑内5的水平可检测到并有活性。
