化学
莫达非尼
多巴胺转运体
多巴胺
运输机
药理学
安非他明
多巴胺摄取抑制剂
再摄取抑制剂
再摄取
去甲肾上腺素转运体
血清素转运体
神经毒性
部分
立体化学
血清素
生物化学
神经科学
多巴胺能
心理学
毒性
受体
医学
有机化学
基因
作者
Predrag Kalaba,Nilima Y. Aher,Marija Ilić,Vladimir Dragačević,Marcus Wieder,András G. Miklósi,Martin Zehl,Judith Wackerlig,Alexander Roller,Tetyana Beryozkina,Bojana Radoman,Sivaprakasam R. Saroja,Wolfgang Lindner,E R Gonzalez,В. А. Бакулев,Johann Leban,Harald H. Sitte,Ernst Urban,Thierry Langer,Gert Lübec
标识
DOI:10.1021/acs.jmedchem.7b01313
摘要
Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds.
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