Relationships between ligand affinities for the cerebellar cannabinoid receptor CB1 and the induction of GDP/GTP exchange.

The hypothesis of these studies is that ligand efficacy at the neuronal CB1 receptor is dependent on the ratio of ligand affinities for the active and inactive states of the receptor. Agonist efficacy was determined in rat cerebellar membranes using agonist-induced guanosine 5'-O-(3-[35S]thiotriphosphate) binding; efficacy was variable among the CB1 agonists examined. Ligand affinities for the active and inactive state of the CB1 receptor were determined by competition with [3H]CP55940 and [3H]SR141716A in the presence of 5'-guanylylimidodiphosphate, respectively. All of the agonists investigated had a higher affinity for the active state than the inactive state. The fraction of CB1 receptors in the active state at a maximally effective concentration was calculated for each agonist and was found to correlate significantly with agonist efficacy. These studies demonstrate that the CB1 receptor of the cerebellum can assume an active conformation in the absence of agonist and that the variability in efficacy among CB1 receptor agonists can be explained by the relative affinities of these ligands for the CB1 receptor in the active and inactive states.