Evidence for inverse agonism of SR141716A at human recombinant cannabinoid CB1 and CB2 receptors.
The cannabinoid receptor antagonist SR141716A has been suggested to be an inverse agonist at CB1 receptors in some isolated intact tissues. We found that the basal incorporation of [35S]-GTPgammaS in Chinese hamster ovary cells expressing human recombinant CB1 and CB2 receptors was inhibited by SR141716A (mean pEC50s 8.26 and 6.00, respectively), whereas cannabinol (10 microM) had no significant effect at hCB1 receptors but inhibited the binding at hCB2 receptors. As cannabinol had no effect on basal [35S]-GTPmicroS binding at hCB1 at a concentration 100 fold higher than its binding affinity (K = 0.1 microM), we conclude that endogenous cannabinoid receptor agonists are not a confounding factor and suggest the actions of SR141716A at the hCB1 receptor, and the actions of SR141716A and cannabinol at the hCB2 receptor, are due to inverse agonism.
MacLennan
S J
SJ
Department of Molecular Pharmacology, Center for Biological Research, Roche Bioscience, Palo Alto, CA 94304, USA.
Reynen
P H
PH
Kwan
J
J
Bonhaus
D W
DW
D000818:Animals; D016466:CHO Cells; D002186:Cannabinoids / Q000378:metabolism*; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D000077285:Rimonabant
D002186:Cannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D011994:Recombinant Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000077285:Rimonabant