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[beta]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]GTPgammaS 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]GTPgammaS 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.
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[beta]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]GTPgammaS 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]GTPgammaS 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.
Authors: L Hanus; A Breuer; S Tchilibon; S Shiloah; D Goldenberg; M Horowitz; R G Pertwee; R A Ross; R Mechoulam; E Fride Journal: Proc Natl Acad Sci U S A Date: 1999-12-07 Impact factor: 11.205
Authors: M Bouaboula; C Poinot-Chazel; J Marchand; X Canat; B Bourrié; M Rinaldi-Carmona; B Calandra; G Le Fur; P Casellas Journal: Eur J Biochem Date: 1996-05-01
Authors: M Beltramo; N Bernardini; R Bertorelli; M Campanella; E Nicolussi; S Fredduzzi; A Reggiani Journal: Eur J Neurosci Date: 2006-03 Impact factor: 3.386
Authors: Ravil R Petrov; Lindsay Knight; Shao-Rui Chen; Jim Wager-Miller; Steven W McDaniel; Fanny Diaz; Francis Barth; Hui-Lin Pan; Ken Mackie; Claudio N Cavasotto; Philippe Diaz Journal: Eur J Med Chem Date: 2013-09-29 Impact factor: 6.514