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 CBI receptors in some isolated intact tissues. We found that the basal incorporation of [S-35]-GTP gamma S in Chinese hamster ovary cells expressing human recombinant CB(1 )and CB2 receptors was inhibited by SR141716A (mean PEC(50)s 8.26 and 6.00, respectively), whereas cannabinol (10 mu M) had no significant effect at hCB(1) receptors but inhibited the binding at hCB(2) receptors. As cannabinol had no effect on basal [S-35]-GTP gamma S binding at hCB1 at a concentration 100 fold higher than its binding affinity (K-i=0.l mu M), we conclude that endogenous cannabinoid receptor agonists are not a confounding factor and suggest the actions of SR141716A at the hCB(1) receptor, and the actions of SR141716A and cannabinol at the hCB(1) receptor, are due to inverse agonism.