کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1365130 | 981552 | 2007 | 16 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters](/preview/png/1365130.png)
Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant properties have been associated with inhibition of the dopamine transporter (DAT) on presynaptic neurons. In the search for medications for cocaine abuse, we have prepared 2-carbomethoxy-3-aryl-8-thiabicyclo[3.2.1]octane analogues of cocaine. We report that this class of compounds provides potent and selective inhibitors of the DAT and SERT. The selectivity resulted from reduced activity at the SERT. The 3β-(3,4-dichlorophenyl) analogue inhibits the DAT and SERT with a potency of IC50 = 5.7 nM and 8.0 nM, respectively. The 3-(3,4-dichlorophenyl)-2,3-unsaturated analogue inhibits the DAT potently (IC50 = 4.5 nM) and selectively (>800-fold vs SERT). Biological enantioselectivity of DAT inhibition was limited for both the 3-aryl-2,3-unsaturated and the 3α-aryl analogues (2-fold), but more robust (>10-fold) for the 3β-aryl analogues. The (1R)-configuration provided the eutomers.
2-Carbomethoxy-3-aryl-8-thiabicyclo[3.2.1]octane analogues of cocaine provide potent and selective inhibitors of the dopamine and serotonin transporters.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry - Volume 15, Issue 2, 15 January 2007, Pages 1067–1082