Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide
Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide
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DOI：
10.1038/sj.bjp.0704327
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发表时间：
2001-10-01
影响因子：
7.3
通讯作者：
Di Marzo, V
中科院分区：
文献类型：
--
作者：
Bisogno, T;Hanus, L;Di Marzo, V
1 (-)-大麻二酚 (CBD) 是大麻的一种非精神药物成分，可作为抗炎药进行治疗。人们对这种化合物可能的分子靶点知之甚少。我们研究了 CBD 及其一些衍生物是否与辣椒素受体 1 型香草酸受体 (VR1) 或与使内源性大麻素 anandamide (AEA) 失活的蛋白质相互作用。 2 CBD 及其对映体 (+)-CBD 以及通过将 CBD 的 C-7 甲基替换为羟甲基或羧基官能团和/或将 C-5' 戊基替换为二甲基庚基 (DMH) 基团而获得的七种类似物，进行了以下测试： (b) RBL-2H3 细胞对 [C-14]-AEA 的摄取，这是由选择性膜转运蛋白促进的； (c) [C-14]-AEA 通过大鼠脑膜水解，由脂肪酸酰胺水解酶催化。 3 CBD 和 (+)-CBD 均刺激 VR1，EC50=3.2-3.5 mum，最大效果与辣椒素相似，即离子霉素 (4 mum) 效果的 67-70%。 CBD（10 妈妈）使 VR1 对辣椒素的作用不敏感。两种化合物的最大剂量的作用不是相加的。 4 (+)-5'-DMH-CBD 和 (+)-7-羟基-5'-DMH-CBD 抑制 [C-14]-AEA 摄取（IC50=10.0 和 7.0 mum）； (-)-对映异构体的活性稍低（IC50=14.0 和 12.5 muM）。 CBD 和 (+)-CBD 也具有活性（IC50=22.0 和 17.0 mum）。 5 CBD (IC50=27.5 muM)、(+)-CBD (IC50=63.5 muM) 和 (-)-7-羟基-CBD (IC50=34 muM)，但其他类似物 (IC50 > 100 um) 弱抑制 [C-14]-AEA 水解。 6 只有 (+)-异构体对 CB1 和/或 CB2 大麻素受体表现出高亲和力。 7 这些研究结果表明，VR1 受体或内源性 AEA 水平升高可能介导 CBD 及其类似物的一些药理作用。鉴于合成简便、高产率以及对 CB1 和 CB2 受体的弱亲和力，(-)-5'-DMH-CBD 代表了作为 AEA 摄取抑制剂和可能的新治疗剂进一步研究的有价值的候选者。
1 (-)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). 2 CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5 ' pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VRI-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [C-14]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [C-14]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. 3 Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2-3.5 mum, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67-70% of the effect obtained with ionomycin (4 mum). CBD (10 mum) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive. 4 (+)-5 ' -DMH-CBD and (+)-7-hydroxy-5 ' -DMH-CBD inhibited [C-14]-AEA uptake (IC50=10.0 and 7.0 mum); the (-)-enantiomers were slightly less active (IC50=14.0 and 12.5 muM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 mum). 5 CBD (IC50=27.5 mum), (+)-CBD (IC50=63.5 muM) and (-)-7-hydroxy-CBD (IC50=34 mum), but not the other analogues (IC50 > 100 um), weakly inhibited [C-14]-AEA hydrolysis. 6 Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. 7 These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (-)-5 ' -DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.