Abstract：
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.
摘要：
大麻素CB2R激动剂由于其非精神活性的性质，作为精神疾病的潜在新疗法已经获得了相当大的关注。与CB1R激动剂相反。在这项研究中,我们利用分子对接设计和合成了23种大麻二酚(CBD)衍生物,目的是发现有效的CB2R激动剂,而不是CB2R拮抗剂或反向激动剂.结构-活性关系（SAR）研究强调了C-3'位点的酰胺基团和C-4'位点的环烷基对于CB2R活化的至关重要性。有趣的是,三个CBD衍生物，即2o，6g,6h,对CB2受体表现出实质性的部分激动活性，与CBD的相反激动性质相反。其中,充当CB2R和5-HT1AR双重激动剂，尽管对CB1R有一些不希望的拮抗剂活性。它表现出显著的CB2R部分激动作用,同时保持与CBD相似的5-HT1AR激动和CB1R拮抗活性水平。药代动力学实验证实其具有有利的药代动力学性质。行为研究进一步揭示,在保持良好的安全性特征的同时,引发显著的抗抑郁药样和抗焦虑药样作用。
