Yang Wenjiao, Sun Haiguo, Ji Jing, Chen Hai, Cheng Jiaxin, Hu Zhengtao, Gong Xudong, Liu Qi, Peng Su, Suo Jin, Hu Tianwen, Tian Guanghui, Shen Jingshan, Hou Qiongqiong, He Yang, Aisa Haji Akber
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Vigonvita Shanghai Co., Ltd, Shanghai 201210, China.
J Med Chem. 2025 Jul 10;68(13):13335-13357. doi: 10.1021/acs.jmedchem.4c03220. Epub 2025 Jun 20.
Emerging evidence suggests that compounds possessing both CB receptor (CBR) agonist and TRPM8 antagonist activities may offer effective pain relief while minimizing the severe side effects commonly associated with current analgesics. In this study, we designed and synthesized a series of novel cannabigerol () derivatives with the goal of identifying potent dual ligands that act as both CBR agonists and TRPM8 antagonists. Structure-activity relationship studies revealed that the introduction of an amide group at the C-2 position or alkylation at the C-3 position of is essential for enhancing CBR agonistic and TRPM8 antagonistic activities. amides and exhibited dual activity as CBR agonists and TRPM8 antagonists, displaying notable anti-inflammatory and analgesic efficacy alongside a favorable safety profile. Notably, compound , a prodrug of , demonstrated improved oral plasma exposure and enhanced analgesic effects in mice.
新出现的证据表明，同时具有大麻素受体（CBR）激动剂和瞬时受体电位香草酸亚型8（TRPM8）拮抗剂活性的化合物可能在有效缓解疼痛的同时，将当前镇痛药常见的严重副作用降至最低。在本研究中，我们设计并合成了一系列新型大麻二酚（）衍生物，目的是鉴定出兼具CBR激动剂和TRPM8拮抗剂作用的强效双重配体。构效关系研究表明，在的C-2位引入酰胺基团或在C-3位进行烷基化对于增强CBR激动活性和TRPM8拮抗活性至关重要。酰胺和表现出作为CBR激动剂和TRPM8拮抗剂的双重活性，显示出显著的抗炎和镇痛功效以及良好的安全性。值得注意的是，化合物作为的前药，在小鼠中表现出改善的口服血浆暴露和增强的镇痛效果。
