Carbon-silicon switch led to the discovery of novel synthetic cannabinoids with therapeutic effects in a mouse model of multiple sclerosis
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.
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Conflict of interest statement
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.