Kawai H, Makino Y, Hirobe M, Ohta S
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
J Neurochem. 1998 Feb;70(2):745-51. doi: 10.1046/j.1471-4159.1998.70020745.x.
We designed as candidate metabolites and synthesized two 1-benzyl-1,2,3,4-tetrahydroisoquinoline derivatives containing a dopamine moiety: 1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3',4'DHBnTIQ) and 1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (6,7DHBnTIQ). Both were detected in mouse brain as endogenous amines by gas chromatography/mass spectrometry. 3',4'DHBnTIQ induced parkinsonism in mice when chronically administered intraperitoneally, whereas 6,7DHBnTIQ did not despite the structural similarity of the two compounds. This difference may be related to cellular uptake: In rat striatal synaptosomes, these compounds were intracellularly transported by the dopamine transporter with Km values of 6.14 and 7.82 microM and Vmax values of 214.3 and 112.2 pmol/min/mg of protein, respectively. Thus, endogenous 3',4'DHBnTIQ may be actively transported into dopaminergic neurons and accumulated there, contributing at least in part to the induction of idiopathic Parkinson's disease.
我们设计并合成了两种含多巴胺部分的1-苄基-1,2,3,4-四氢异喹啉衍生物作为候选代谢物：1-(3',4'-二羟基苄基)-1,2,3,4-四氢异喹啉(3',4'DHBnTIQ)和1-苄基-6,7-二羟基-1,2,3,4-四氢异喹啉(6,7DHBnTIQ)。通过气相色谱/质谱法在小鼠脑中检测到这两种物质均为内源性胺类。当长期腹腔注射时，3',4'DHBnTIQ可诱导小鼠出现帕金森症，而尽管这两种化合物结构相似，6,7DHBnTIQ却不会。这种差异可能与细胞摄取有关：在大鼠纹状体突触体中，这些化合物通过多巴胺转运体进行细胞内转运，其Km值分别为6.14和7.82微摩尔，Vmax值分别为214.3和112.2皮摩尔/分钟/毫克蛋白质。因此，内源性3',4'DHBnTIQ可能被主动转运到多巴胺能神经元并在那里积累，至少部分促成特发性帕金森病的发生。
