Sch35966 is a potent, selective agonist at the peripheral cannabinoid receptor (CB2) in rodents and primates

Background and purpose: The peripheral cannabinoid receptor (CB2) is expressed on peripheral immune cells and is thought to have a role in the immunosuppressive effects of cannabinoids. Historically, there have been few potent, CB2-selective agonists to assess the contribution of CB2 to this phenomenon. The studies presented here describe the synthesis of 8,10bis[(2,2-dimethyl-1-oxopropyl) oxy]-11-methyl-1234-tetrahydro-6H-benzo[b]quinolizin-6-one (Sch35966), which binds with low nanomolar potency to CB2 in both primates and rodents. Experimental approach: The affinity, potency and efficacy of Sch35966 and other cannabinoid ligands at CB2 was assessed using competition binding assays vs [H-3]CP55,940,[S-35]GTP gamma S exchange, cAMP accumulation and cell chemotaxis assays. Key results: We showed that Sch35966 has > 450-fold selectivity for CB2 binding vs the central cannabinoid receptor (CB1) in primates (humans and cynomolgus monkeys) and rodents (rats and mice). Sch35966 is an agonist as it effectively inhibited forskolin-stimulated cAMP synthesis in CHO-hCB(2) cells, stimulated [S-35] GTPgS exchange and directed chemotaxis in cell membranes expressing CB2. In all species examined, Sch35966 was more potent, more efficacious and more selective than JWH-015 (a commonly used CB2-selective agonist). Conclusions and implications: Taken together, the data show that Sch35966 is a potent and efficacious CB2-selective agonist in rodents and primates.