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


METHODS
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.


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
Taken together, the data show that Sch35966 is a potent and efficacious CB(2)-selective agonist in rodents and primates.
Gonsiorek
W
W
Department of Inflammation, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Lunn
C A
CA
Fan
X
X
Deno
G
G
Kozlowski
J
J
Hipkin
R W
RW
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002462:Cell Membrane; D002633:Chemotaxis; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D003511:Cyclohexanols; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008252:Macaca fascicularis; D051379:Mice; D011807:Quinolizines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013045:Species Specificity
C523830:8,10-bis((2,2-dimethyl-1-oxopropyl)oxy)-11-methyl-1234-tetrahydro-6H-benzo(beta)quinolizin-6-one; D003511:Cyclohexanols; D007211:Indoles; D011807:Quinolizines; D043885:Receptor, Cannabinoid, CB2; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000242:Cyclic AMP; C062018:HU 211; C402944:JHW 015