Cannabilactones: A novel class of CB2 selective agonists with peripheral analgesic activity
Cannabilactones: A novel class of CB2 selective agonists with peripheral analgesic activity
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DOI：
10.1021/jm070441u
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发表时间：
2007-12-27
影响因子：
7.3
通讯作者：
Makriyannis, Alexandros
中科院分区：
文献类型：
--
作者：
Khanolkar, Atmaram D.;Lu, Dai;Makriyannis, Alexandros
CB2大麻素受体的鉴定为开发治疗有用的大麻素分子提供了新的靶点。我们已经合成了对该受体具有高亲和力和选择性的苯并[c]铬-6- 1类似物。这些新化合物在结构上与大麻酚（6,6,9-三甲基-3-戊基- 6h -苯并[c]铬-1-醇）相关，大麻酚是大麻的一种天然成分，具有适度的CB2选择性。新的选择性激动剂的主要药效特征包括3-（1',1'-二甲基庚基）侧链和大麻素三环结构上的6-氧基团，这类化合物被称为“大麻内酯”。我们的研究结果表明，六元内酯药效团对CB2受体的选择性至关重要。9-羟基类似物5 （AM1714）对CB2受体表现出490倍和亚纳摩尔亲和力的最佳受体亚型选择性，而9-甲氧基类似物4b （AM1710）具有54倍的CB2选择性。x射线。晶体学和分子模型表明，甘薯内酯具有平面环状构象。体外实验表明，这些新化合物是CB2激动剂，而体内实验发现，可比内酯4b和5具有强效的外周镇痛活性。
The identification of the CB2 cannabinoid receptor has provided a novel target for the development of therapeutically useful cannabinergic molecules. We have synthesized benzo[c]chromen-6-one analogs possessing high affinity and selectivity for this receptor. These novel compounds are structurally related to cannabinol (6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol), a natural constituent of cannabis with modest CB2 selectivity. Key pharmacophoric features of the new selective agonists include a 3-(1',1'-dimethylheptyl) side chain and a 6-oxo group on the cannabinoid tricyclic structure that characterizes this class of compounds as "cannabilactones." Our results suggest that the six-membered lactone pharmacophore is critical for CB2 receptor selectivity. Optimal receptor subtype selectivity of 490-fold and subnanomolar affinity for the CB2 receptor is exhibited by a 9-hydroxyl analog 5 (AM1714), while the 9-methoxy analog 4b (AM1710) had a 54-fold CB2 selectivity. X-ray. crystallography and molecular modeling show the cannabilactones to have a planar ring conformation. In vitro testing revealed that the novel compounds are CB2 agonists, while in vivo testing of cannabilactones 4b and 5 found them to possess potent peripheral analgesic activity.