Relative efficacies of cannabinoid CB₁ receptor agonists in the mouse brain

We measured (-)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-phenol (CP 55,940)-, (-)11-OH-Δ⁸-tetrahydrocannabinol-dimethylheptyl (HU-210)-, anandamide- and Δ⁹-tetrahydrocannabinol-stimulated G protein activation in mouse brain using the [³⁵S]GTPγS functional assay. The K(i) values for these drugs were determined by agonist competition binding with the cannabinoid CB, receptor antagonist [³H] N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H -pyrazole-3-carboxamidehydrochloride ([³H]SR141716A). This information was used to calculate the efficacy for drug stimulation of G protein activity, The rank order of efficacy was CP 55,940 > HU-210 > anandamide > Δ⁹-tetrahydrocannabinol with the latter two drugs being partial agonists. Since efficacy values relate receptor occupancy to functional responses, we believe efficacy values are a better measure of drug-mediated functional responses compared with measurements of drug potency.