The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.
The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.
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天然产物木醇作为有效大麻素受体激动剂发展的铅结构。
DOI：
10.1371/journal.pone.0077739
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Müller CE
中科院分区：
文献类型：
--
作者：
Fuchs A;Rempel V;Müller CE
厚朴的主要生物活性成分4-烯丙基-2-(5-烯丙基-2-羟基苯基)苯酚及其主要代谢物四氢厚朴酚可激活大麻素受体。我们现在研究了(四氢)厚朴酚类似物随着烷基链和酚基的变化而产生的构效关系，并能显著提高效力。其中最有效的化合物是Cb1/Cb2完全激动剂2-(2-甲氧基-5-丙基苯基)-4-己基苯酚(61a，KICB1：0.00957微米；KICB2：0.0238微米)，以及CB2选择性部分激动剂2-(2-羟基-5-丙基苯基)-4-戊基苯酚(60，KICB1：0.362微米；KICB2：0.0371微米)，显示出比GPR18和GPR55更高的选择性。化合物61b是61a的异构体，是最有效的GPR55拮抗剂，其IC50值为3.25µM，但不具选择性。这种结构相对简单，没有立体中心，通过四到五步的合成过程就可以很容易地从普通的起始材料中获得。中心反应步骤是精心设计的Suzuki-Miyaura交叉偶联反应，适用于组合化学方法。该支架用途广泛，可以进行微调以获得广泛的受体亲和力、选择性和有效性。
Magnolol (4-allyl-2-(5-allyl-2-hydroxyphenyl)phenol), the main bioactive constituent of the medicinal plant Magnolia officinalis, and its main metabolite tetrahydromagnolol were recently found to activate cannabinoid (CB) receptors. We now investigated the structure-activity relationships of (tetrahydro)magnolol analogs with variations of the alkyl chains and the phenolic groups and could considerably improve potency. Among the most potent compounds were the dual CB1/CB2 full agonist 2-(2-methoxy-5-propyl-phenyl)-4-hexylphenol (61a, K i CB1∶0.00957 µM; K i CB2∶0.0238 µM), and the CB2-selective partial agonist 2-(2-hydroxy-5-propylphenyl)-4-pentylphenol (60, K i CB1∶0.362 µM; K i CB2∶0.0371 µM), which showed high selectivity versus GPR18 and GPR55. Compound 61b, an isomer of 61a, was the most potent GPR55 antagonist with an IC50 value of 3.25 µM but was non-selective. The relatively simple structures, which possess no stereocenters, are easily accessible in a four- to five-step synthetic procedure from common starting materials. The central reaction step is the well-elaborated Suzuki-Miyaura cross-coupling reaction, which is suitable for a combinatorial chemistry approach. The scaffold is versatile and may be fine-tuned to obtain a broad range of receptor affinities, selectivities and efficacies.
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DOI：
10.1073/pnas.0803601105
发表时间：
2008-07-01
影响因子：
11.1
作者：
Gertsch, Juerg;Leonti, Marco;Zimmer, Andreas
通讯作者：
Zimmer, Andreas
影响因子：
1.8
作者：
MIYAURA, N;YAMADA, K;SUZUKI, A
通讯作者：
SUZUKI, A
影响因子：
3.2
作者：
Bisogno, T.
通讯作者：
Bisogno, T.
影响因子：
4.8
作者：
Henstridge, Christopher M.;Balenga, Nariman A. B.;Irving, Andrew J.
通讯作者：
Irving, Andrew J.
影响因子：
4.8
作者：
Anavi-Goffer, Sharon;Baillie, Gemma;Ross, Ruth A.
通讯作者：
Ross, Ruth A.