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

Abstract

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 [ 3H]CP55,940, [ 35S]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 [ 35S]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. © 2007 Nature Publishing Group All rights reserved.