3β-(4'-氨基苯基)-2β-托烷甲醇的2,3-环类似物的合成及单胺转运体结合特性

Synthesis and monoamine transporter binding properties of 2,3-cyclo analogues of 3beta-(4'-aminophenyl)-2beta-tropanemethanol.

作者信息

Carroll F Ivy, Blough Bruce E, Huang Xiaodong, Nie Zhe, Mascarella S Wayne, Deschamps Jeffrey, Navarro Hernán A

机构信息

Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, USA.

出版信息

J Med Chem. 2006 Jul 27;49(15):4589-94. doi: 10.1021/jm060287w.

DOI:10.1021/jm060287w

PMID:16854064

Abstract

A series of cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol analogues (5a-m) possessing varying linker groups between the 2- and 3-position on the tropane ring were synthesized and evaluated for their monoamine transporter binding properties. The results show that binding to the dopamine and serotonin transporters (DAT and 5-HTT) is highly dependent on the specific linker used. Cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol pimelic acid ester/amide (5b) had an IC50 of 3.8 nM at the DAT. Cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol sebacic acid ester/amide (5e) had a Ki of 1.9 nM at the 5-HTT and was 68- and 737-fold selective for the 5-HTT relative to the DAT and NET. Small changes to the size as well as the electrostatic and hydrophobic properties of the 2,3-linker in 5b or 5e led to much less potent analogues at all three transporters. These results suggest that the high affinity for 5b and 5e at the DAT and 5-HTT may be due to their specific conformational properties.

摘要

合成了一系列在托烷环2位和3位之间具有不同连接基团的环-3β-(4-氨基苯基)-2β-托烷甲醇类似物(5a - m)，并对其单胺转运体结合特性进行了评估。结果表明，与多巴胺和5-羟色胺转运体（DAT和5-HTT）的结合高度依赖于所使用的特定连接基团。环-3β-(4-氨基苯基)-2β-托烷甲醇庚二酸酯/酰胺(5b)在DAT上的IC50为3.8 nM。环-3β-(4-氨基苯基)-2β-托烷甲醇癸二酸酯/酰胺(5e)在5-HTT上的Ki为1.9 nM，相对于DAT和去甲肾上腺素转运体（NET），其对5-HTT的选择性分别为68倍和737倍。对5b或5e中2,3-连接基团的大小以及静电和疏水性质进行微小改变，会导致所有三种转运体的类似物活性大大降低。这些结果表明，5b和5e对DAT和5-HTT的高亲和力可能归因于它们特定的构象性质。