香豆素衍生物的合成及构效关系研究作为潜在的大麻素受体激动剂。
Synthesis and SAR evaluation of coumarin derivatives as potent cannabinoid receptor agonists.
机构信息
Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, D-76131, Karlsruhe, Germany; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC, Leiden, the Netherlands.
Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, D-76131, Karlsruhe, Germany; Institute of Biological and Chemical Systems - Functional Molecular Systems, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, D-76344, Eggenstein-Leopoldshafen, Germany.
出版信息
Eur J Med Chem. 2021 Aug 5;220:113354. doi: 10.1016/j.ejmech.2021.113354. Epub 2021 Apr 7.
We report the development and extensive structure-activity relationship evaluation of a series of modified coumarins as cannabinoid receptor ligands. In radioligand, and [S]GTPγS binding assays the CB receptor binding affinities and efficacies of the new ligands were determined. Furthermore, we used a ligand-based docking approach to validate the empirical observed results. In conclusion, several crucial structural requirements were identified. The most potent coumarins like 3-butyl-7-(1-butylcyclopentyl)-5-hydroxy-2H-chromen-2-one (36b, K CB 13.7 nM, EC 18 nM), 7-(1-butylcyclohexyl)-5-hydroxy-3-propyl-2H-chromen-2-one (39b, K CB 6.5 nM, EC 4.51 nM) showed a CB selective agonistic profile with low nanomolar affinities.
我们报告了一系列修饰香豆素作为大麻素受体配体的开发和广泛的结构-活性关系评估。在放射性配体和[S]GTPγS 结合测定中，确定了新配体的 CB 受体结合亲和力和效力。此外，我们使用基于配体的对接方法来验证经验观察结果。总之，确定了几个关键的结构要求。最有效的香豆素，如 3-丁基-7-(1-丁基环戊基)-5-羟基-2H-色烯-2-酮（36b，K CB 13.7 nM，EC 18 nM）、7-(1-丁基环己基）-5-羟基-3-丙基-2H-色烯-2-酮（39b，K CB 6.5 nM，EC 4.51 nM），具有低纳摩尔亲和力的 CB 选择性激动作用。
Zotero 插件