Evidence for inverse agonism of SR141716A at human recombinant cannabinoid CB₁ and CB₂ receptors

Abstract

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]-GTPγS 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 μM) had no significant effect at hCB₁ receptors but inhibited the binding at hCB₂ receptors. As cannabinol had no effect on basal [³⁵S]-GTPγS binding at hCB₁ at a concentration 100 fold higher than its binding affinity (K_i=0.1 μM), 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.

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