化学
反激动剂
抗焦虑药
部分激动剂
药理学
竞争行为
兴奋剂
内在活性
利莫那班
受体
大麻素受体
立体化学
心理学
生物化学
医学
精神科
侵略
作者
Wenhui Yang,Xudong Gong,Haiguo Sun,Chunhui Wu,Jishuan Suo,Jing Ji,Xiangrui Jiang,Jingshan Shen,He Yang,Haji Akbar Aisa
标识
DOI:10.1016/j.ejmech.2023.116048
摘要
Cannabinoid CB2R agonists have gained considerable attention as potential novel therapies for psychiatric disorders due to their non-psychoactive nature, in contrast to CB1R agonists. In this study, we employed molecular docking to design and synthesize 23 derivatives of cannabidiol (CBD) with the aim of discovering potent CB2R agonists rather than CB2R antagonists or inverse agonists. Structure-activity relationship (SAR) investigations highlighted the critical importance of the amide group at the C-3' site and the cycloalkyl group at the C-4' site for CB2R activation. Interestingly, three CBD derivatives, namely 2o, 6g, and 6h, exhibited substantial partial agonistic activity towards the CB2 receptor, in contrast to the inverse agonistic property of CBD. Among these, 2o acted as a CB2R and 5-HT1AR dual agonist, albeit with some undesired antagonist activity for CB1R. It demonstrated significant CB2R partial agonism while maintaining a level of 5-HT1AR agonistic and CB1R antagonistic activity similar to CBD. Pharmacokinetic experiments confirmed that 2o possesses favorable pharmacokinetic properties. Behavioral studies further revealed that 2o elicits significant antidepressant-like and anxiolytic-like effects while maintaining a good safety profile.
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