化学
多巴胺
前药
多巴胺转运体
药理学
左旋多巴
酪氨酸
连接器
IC50型
酪氨酸羟化酶
儿茶酚胺
生物化学
运输机
体外
酶
帕金森病
内科学
医学
操作系统
基因
疾病
计算机科学
作者
Nikki A. Thiele,Jussi M. Kärkkäinen,Kenneth B. Sloan,Jarkko Rautio,Kristiina M. Huttunen
标识
DOI:10.1016/j.bmcl.2018.07.030
摘要
To achieve the sustained release of dopamine in the brain for the symptomatic treatment of Parkinson’s disease, dopamine was conjugated to l-tyrosine, an l-type amino acid transporter 1 (LAT1)-targeting vector, using a secondary carbamate linker. The resulting prodrug, dopa-CBT, inhibited the uptake of the LAT1 substrate [14C]-l-leucine in LAT1-expressing MCF-7 cells with an IC50 value of 28 µM, which was 3.5-times lower than that of the gold standard for dopamine replacement therapy, l-dopa (IC50 ca. 100 µM). Despite its high affinity for LAT1, dopa-CBT was transported via LAT1 into MCF-7 cells 850-times more slowly (Vmax < 3 pmol/min/mg) than l-dopa (Vmax 2.6 nmol/min/mg), most likely due to its large size compared to l-dopa. However, dopa-CBT was significantly more stable in 10% rat liver homogenate than l-dopa, releasing dopamine and l-tyrosine, an endogenous dopamine precursor, slowly, which indicates that it may serve as a dual carrier of dopamine across the blood-brain barrier selectively expressing LAT1.
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