Sch35966 is a potent, selective agonist at the peripheral cannabinoid receptor (CB 2 ) in rodents and primates

Background and purpose: The peripheral cannabinoid receptor (CB 2 ) 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, CB 2 ‐selective agonists to assess the contribution of CB 2 to this phenomenon. The studies presented here describe the synthesis of 8,10‐bis[(2,2‐dimethyl‐1‐oxopropyl)oxy]‐11‐methyl‐1234‐tetrahydro‐6H‐benzo[β]quinolizin‐6‐one (Sch35966), which binds with low nanomolar potency to CB 2 in both primates and rodents. Experimental approach: The affinity, potency and efficacy of Sch35966 and other cannabinoid ligands at CB 2 was assessed using competition binding assays vs [ 3 H]CP55,940, [ 35 S]GTPγS exchange, cAMP accumulation and cell chemotaxis assays. Key results: We showed that Sch35966 has >450‐fold selectivity for CB 2 binding vs the central cannabinoid receptor (CB 1 ) 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 [ 35 S]GTPγS exchange and directed chemotaxis in cell membranes expressing CB 2 . In all species examined, Sch35966 was more potent, more efficacious and more selective than JWH‐015 (a commonly used CB 2 ‐selective agonist). Conclusions and implications: Taken together, the data show that Sch35966 is a potent and efficacious CB 2 ‐selective agonist in rodents and primates. British Journal of Pharmacology (2007) 151 , 1262–1271; doi: 10.1038/sj.bjp.0707336