Synthesis and SAR evaluation of coumarin derivatives as potent cannabinoid receptor agonists

Mohr Florian; Hurrle Thomas; Burggraaff Lindsey; Langer Lukas; Bemelmans Martijn P.; Knab Maximilian; Nieger Martin; van Westen Gerard J. P.; Heitman Laura H.; Braese Stefan

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Synthesis and SAR evaluation of coumarin derivatives as potent cannabinoid receptor agonists

机译：香豆素衍生物作为有效大麻素受体激动剂的合成及SAR评价

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We report the development and extensive structure-activity relationship evaluation of a series of modified coumarins as cannabinoid receptor ligands. In radioligand, and [S-35]GTP gamma S 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-i CB2 13.7 nM, EC50 18 nM), 7-(1-butylcyclohexyl)-5-hydroxy-3-propyl-2H-chromen-2-one (39b, K-i CB2 6.5 nM, EC50 4.51 nM) showed a CB2 selective agonistic profile with low nanomolar affinities. (C) 2021 Published by Elsevier Masson SAS.

机译：我们报道了一系列改性香豆素作为大麻素受体配体的开发和广泛的构效关系评估。在放射性配体和[S-35]GTPγS结合试验中，测定了新配体的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。最有效的香豆素类化合物如3-丁基-7-（1-丁基环戊基）-5-羟基-2H-铬-2-酮（36b，K-i CB2 13.7 nM，EC50 18 nM），7-（1-丁基环己基）-5-羟基-3-丙基-2H-铬-2-酮（39b，K-i CB2 6.5 nM，EC50 4.51 nM）显示出具有低纳摩尔亲和力的CB2选择性激动剂谱。（c）2021由爱思唯尔马松SAS出版。

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来源
《European Journal of Medicinal Chemistry: Chimie Therapeutique》 |2021年第1期|共9页
作者
Mohr Florian; Hurrle Thomas; Burggraaff Lindsey; Langer Lukas; Bemelmans Martijn P.; Knab Maximilian; Nieger Martin; van Westen Gerard J. P.; Heitman Laura H.; Braese Stefan;
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作者单位

Karlsruhe Inst Technol KIT Inst Organ Chem Fritz Haber Weg 6 D-76131 Karlsruhe Germany;

Karlsruhe Inst Technol KIT Inst Organ Chem Fritz Haber Weg 6 D-76131 Karlsruhe Germany;

Leiden Univ Leiden Acad Ctr Drug Res Div Drug Discovery &

Safety Einsteinweg 55 NL-2333 CC;

Karlsruhe Inst Technol KIT Inst Organ Chem Fritz Haber Weg 6 D-76131 Karlsruhe Germany;

Leiden Univ Leiden Acad Ctr Drug Res Div Drug Discovery &

Safety Einsteinweg 55 NL-2333 CC;

Karlsruhe Inst Technol KIT Inst Organ Chem Fritz Haber Weg 6 D-76131 Karlsruhe Germany;

Univ Helsinki Dept Chem POB 55 AI Virtasen Aukio 1 Helsinki 00014 Finland;

Leiden Univ Leiden Acad Ctr Drug Res Div Drug Discovery &

Safety Einsteinweg 55 NL-2333 CC;

Leiden Univ Leiden Acad Ctr Drug Res Div Drug Discovery &

Safety Einsteinweg 55 NL-2333 CC;

Karlsruhe Inst Technol KIT Inst Organ Chem Fritz Haber Weg 6 D-76131 Karlsruhe Germany;

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原文格式 PDF
正文语种 eng
中图分类药学;
关键词
CB receptors; Synthetic cannabinoids; Coumarins; CB2 agonists; Endocannabinoid system; Radioligand binding assays;

机译：CB受体;合成大麻素;香豆素类;CB2激动剂;内源性大麻素系统;放射性配基结合分析;

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Synthesis and SAR evaluation of coumarin derivatives as potent cannabinoid receptor agonists

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