Carbon-silicon switch led to the discovery of novel synthetic cannabinoids with therapeutic effects in a mouse model of multiple sclerosis

Wenwen Duan; Ying Sun; Meng Wu; Zhiyuan Zhang; Taotao Zhang; Huan Wang; Fei Li; Lingyun Yang; Yueming Xu; Zhi-Jie Liu; Tian Hua; Hong Nie; Jianjun Cheng

doi:10.1016/j.ejmech.2021.113878

Carbon-silicon switch led to the discovery of novel synthetic cannabinoids with therapeutic effects in a mouse model of multiple sclerosis

Eur J Med Chem. 2021 Dec 15:226:113878. doi: 10.1016/j.ejmech.2021.113878. Epub 2021 Oct 5.

Authors

Wenwen Duan¹, Ying Sun², Meng Wu¹, Zhiyuan Zhang¹, Taotao Zhang³, Huan Wang¹, Fei Li¹, Lingyun Yang¹, Yueming Xu¹, Zhi-Jie Liu⁴, Tian Hua⁵, Hong Nie⁶, Jianjun Cheng⁷

Affiliations

¹ iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
² Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
³ Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, China.
⁴ iHuman Institute, ShanghaiTech University, Shanghai, 201210, China; School of Life Sciences and Technology, ShanghaiTech University, Shanghai, 201210, China.
⁵ iHuman Institute, ShanghaiTech University, Shanghai, 201210, China; School of Life Sciences and Technology, ShanghaiTech University, Shanghai, 201210, China. Electronic address: huatian@shanghaitech.edu.cn.
⁶ Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: hine@sjtu.edu.cn.
⁷ iHuman Institute, ShanghaiTech University, Shanghai, 201210, China. Electronic address: chengjj@shanghaitech.edu.cn.

PMID: 34634742
DOI: 10.1016/j.ejmech.2021.113878

Abstract

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.

Keywords: Cannabidiol; Cannabinoid; G protein-coupled receptor; Multiple sclerosis; Tetrahydrocannabinol.

MeSH terms

Animals
Cannabinoids / chemical synthesis
Cannabinoids / chemistry
Cannabinoids / pharmacology*
Carbon / chemistry*
Disease Models, Animal*
Dose-Response Relationship, Drug
Drug Discovery
Encephalomyelitis, Autoimmune, Experimental / drug therapy*
Encephalomyelitis, Autoimmune, Experimental / metabolism
Encephalomyelitis, Autoimmune, Experimental / pathology
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Multiple Sclerosis / drug therapy*
Multiple Sclerosis / metabolism
Multiple Sclerosis / pathology
Receptor, Cannabinoid, CB1 / agonists
Receptor, Cannabinoid, CB1 / metabolism
Receptor, Cannabinoid, CB2 / agonists
Receptor, Cannabinoid, CB2 / metabolism
Silicon / chemistry*
Structure-Activity Relationship

Substances

Cannabinoids
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Carbon
Silicon