Cannabidiol-2′,6′-Dimethyl Ether, a Cannabidiol Derivative, Is a Highly Potent and Selective 15-Lipoxygenase Inhibitor
Cannabidiol-2′,6′-Dimethyl Ether, a Cannabidiol Derivative, Is a Highly Potent and Selective 15-Lipoxygenase Inhibitor
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DOI：
10.1124/dmd.109.026930
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发表时间：
2009-08-01
影响因子：
3.9
通讯作者：
Watanabe, Kazuhito
中科院分区：
文献类型：
--
作者：
Takeda, Shuso;Usami, Noriyuki;Watanabe, Kazuhito
去甲二氢愈创木酸（NDGA）（一种非选择性脂氧合酶（LOX）抑制剂）介导的15-LOX抑制的抑制作用已被报道受到其儿茶酚环的修饰（例如羟基的甲基化）的影响。大麻二酚（CBD）是大麻的主要成分之一，已知可抑制LOX活性。基于在NDGA中观察到的现象，我们研究了CBD的甲基化是否影响其对15-LOX的抑制潜力，因为CBD含有间苯二酚环，这是儿茶酚的异构体。虽然CBD抑制15-LOX活性的IC 50值（50%抑制浓度）为2.56 μ M，但其单甲基化和二甲基化衍生物CBD-2 '-单甲醚和CBD-2'，6 '-二甲醚（CBDD）比CBD更强地抑制15-LOX活性。CBD（作为原型）的间苯二酚部分中的甲基数目似乎是抑制15-LOX的效力和选择性的关键决定因素。CBDD对15-LOX抑制的IC 50值为0.28 μ M，对15-LOX的抑制选择性（即，5-LOX/15-LOX比值的IC 50值）大于700。在LOX同种型中，已知15-LOX能够抑制低密度脂蛋白（LDL）颗粒中的胆固醇酯（即，氧化LDL的形成）。因此，15-LOX被认为参与动脉粥样硬化的发展，CBDD可能是用于生产动脉粥样硬化药物的有用原型。
The inhibitory effect of nordihydroguaiaretic acid (NDGA) (a nonselective lipoxygenase (LOX) inhibitor)-mediated 15-LOX inhibition has been reported to be affected by modification of its catechol ring, such as methylation of the hydroxyl group. Cannabidiol (CBD), one of the major components of marijuana, is known to inhibit LOX activity. Based on the phenomenon observed in NDGA, we investigated whether or not methylation of CBD affects its inhibitory potential against 15-LOX, because CBD contains a resorcinol ring, which is an isomer of catechol. Although CBD inhibited 15-LOX activity with an IC50 value (50% inhibition concentration) of 2.56 mu M, its monomethylated and dimethylated derivatives, CBD-2'-monomethyl ether and CBD-2',6'-dimethyl ether (CBDD), inhibited 15-LOX activity more strongly than CBD. The number of methyl groups in the resorcinol moiety of CBD (as a prototype) appears to be a key determinant for potency and selectivity in inhibition of 15-LOX. The IC50 value of 15-LOX inhibition by CBDD is 0.28 mu M, and the inhibition selectivity for 15-LOX (i.e., the 5-LOX/15-LOX ratio of IC50 values) is more than 700. Among LOX isoforms, 15-LOX is known to be able to oxygenate cholesterol esters in the low-density lipoprotein (LDL) particle (i.e., the formation of oxidized LDL). Thus, 15-LOX is suggested to be involved in development of atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.