化学
单胺类神经递质
药代动力学
体内
囊泡单胺转运体
药理学
立体化学
生物利用度
对接(动物)
运输机
川芎嗪
对映体
生物化学
多巴胺
生物
医学
血清素
内科学
受体
生物技术
护理部
基因
作者
Wenyan Wang,Shilan Lin,Guangying Du,Xinfa Bai,Jing Lu,Liang Ye,Hongbo Wang,Rui Zhang,Jingwei Tian
出处
期刊:Future Medicinal Chemistry
[Newlands Press Ltd]
日期:2022-07-01
卷期号:14 (13): 991-1003
标识
DOI:10.4155/fmc-2021-0331
摘要
Aim: To separate and evaluate 9-cyclopropylmethoxy-dihydrotetrabenazine (13a) and its stereoisomers for their high affinity for vesicular monoamine transporter-2 (VMAT2). Method: Stereoisomers of 13a were separated and configurations were ascertained by chiral chromatography and crystal diffraction combined with 1H-1H NOESY assay. Possible binding modes of eight stereoisomers and VMAT2 were explored by molecular docking assays. The VMAT2 affinity of the stereoisomers, inhibition in vivo and pharmacokinetics in rats were evaluated. Results: Three stereoisomers were obtained: P1, P2 and P3, and all had similar VMAT2 binding modes. P2 [(2R, 3R, 11bR)-13a] showed the highest potential VMAT2 binding activity (Ki = 0.75 nM), decreased locomotor activity in rats and had an oral absolute bioavailability of 92.0%. Conclusion: P2 has good efficacy and pharmacokinetic properties and warrants further development to treat tardive dyskinesia.
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