Separation of cannabinoid receptor affinity and efficacy in delta-8-tetrahydrocannabinol side-chain analogues.

1 The activities of a number of side-chain analogues of delta-8-tetrahydrocannabinol (Delta (8)-THC) in rat cerebellar membrane preparations were tested. 2 The affinities of each compound for the CB1 receptor were compared by their respective abilities to displace [H-3]-SR141716A and their efficacies compared by stimulation of [S-35]-GTP gammaS binding. 3 It was found that the affinities varied from 0.19+/-0.03 nhl for 3-norpentyl-3-[6'-cyano,1',1'-dimethyl]hexyl-Delta (8)-THC to 395 +/- 66.3 nM for 5'-[N-(4-chlorophenyl)]-1',1'-dimethyl-carboxamido-Delta (8)-THC. 4 The efficacies of these compounds varied greatly, ranging from the very low efficacy exhibited to acetylenic compounds such as 1'-heptyn-Delta (8)-THC and 4'-octyn-Delta (8)-THC to higher efficacy compounds such as 5'-(4-cyanophenoxy)-1',1'-dimethyl-Delta (8)-THC and 5'-[N-(4-aminosulphonylphenyl)]-1',1' dimethyl-carboxamido Delta (8)-THC. All agonist activities were antagonized by the CB1-selective antagonist SR141716A. 5 It was found that a ligand's CB1 affinity and efficacy are differentially altered by modifications in the side-chain. Decreasing the flexibility of the side-chain reduced efficacy but largely did not alter affinity. Additionally, the positioning of electrostatic moieties. such as cyano groups. within the sidechain also has contrasting effects on these two properties. 6 In summary, this report details the characterization of a number of novel Delta (8)-THC analogues in rat cerebellar membranes. It provides the first detailed pharmacological analysis of how the inclusion of electrostatic moieties in the side-chain and also how alteration of the side-chain's flexibility may differentially affect a CB1 cannabinoid receptor ligand's affinity and efficacy.