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

Abstract

1. The activities of a number of side-chain analogues of delta-8-tetrahydrocannabinol (Δ8-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 [3H]-SR141716A and their efficacies compared by stimulation of [35S]-GTPγS binding. 3. It was found that the affinities varied from 0.19±0.03 nM for 3-norpentyl-3-[6′-cyano,1′,1′dimethyl]hexyl-Δ 8-THC to 395±66.3 nM for 5′-[N-(4-chlorophenyl)]-1′,1′-dimethyl-carboxamido-Δ 8-THC. 4. The efficacies of these compounds varied greatly, ranging from the very low efficacy exhibited to acetylenic compounds such as 1′-heptyn-Δ8-THC and 4′-octyn-Δ8-THC to higher efficacy compounds such as 5′-(4-cyanophenoxy)-1′,1′-dimethyl-Δ8-THC and 5′-[N-(4-aminosulphonylphenyl)]-1′,1′ dimethyl-carboxamido Δ8-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 side-chain also has contrasting effects on these two properties. 6. In summary, this report details the characterization of a number of novel Δ8-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.