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Carbon-silicon switch led to the discovery of novel synthetic cannabinoids with therapeutic effects in a mouse model of multiple sclerosis
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2021-10-05 , DOI: 10.1016/j.ejmech.2021.113878
Wenwen Duan 1 , Ying Sun 2 , Meng Wu 1 , Zhiyuan Zhang 1 , Taotao Zhang 3 , Huan Wang 1 , Fei Li 1 , Lingyun Yang 1 , Yueming Xu 1 , Zhi-Jie Liu 4 , Tian Hua 4 , Hong Nie 2 , Jianjun Cheng 1
Affiliation  

Cannabinoids are widely studied as therapeutic agents for the treatment of various diseases. Among them, THC and CBD are two important phytocannabinoids which have served as structural templates for the design of synthetic analogs. In this study, we designed and synthesized a variety of novel cannabinoids based on the structural backbones of THC and CBD using the carbon-silicon switch strategy. A dimethyl silyl group was introduced as the tail group and two series of novel compounds were designed and synthesized, which showed a wide range of binding affinity for CB1 and CB2 receptors. Among them, compound 15b was identified as a non-selective CB1 and CB2 agonist and 38b as a selective agonist for the CB2 receptor. Preliminary screening showed that both compounds have improved metabolic stability than their carbon analogs and good in vivo pharmacokinetic profiles. Furthermore, both 15b and 38b significantly alleviated the phenotype of experimental autoimmune encephalomyelitis (EAE) in mice.



中文翻译:

碳硅开关导致在多发性硬化症小鼠模型中发现具有治疗作用的新型合成大麻素

大麻素作为治疗剂被广泛研究用于治疗各种疾病。其中,THC 和 CBD 是两种重要的植物大麻素,可作为合成类似物设计的结构模板。在这项研究中,我们利用碳硅转换策略,基于 THC 和 CBD 的结构骨架设计并合成了多种新型大麻素。引入二甲基甲硅烷基作为尾基,设计合成了两个系列的新型化合物,对CB1和CB2受体具有广泛的结合亲和力。其中,化合物15b被鉴定为非选择性 CB1 和 CB2 激动剂和38b作为 CB2 受体的选择性激动剂。初步筛选表明,这两种化合物都比它们的碳类似物具有改善的代谢稳定性和良好的体内药代动力学特征。此外,15b38b均显着减轻了小鼠实验性自身免疫性脑脊髓炎 (EAE) 的表型。

更新日期:2021-10-06
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