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

The activities of a number of side‐chain analogues of delta‐8‐tetrahydrocannabinol (Δ8‐THC) in rat cerebellar membrane preparations were tested. 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. It was found that the affinities varied from 0.19±0.03 nM for 3‐norpentyl‐3‐[6′‐cyano,1′,1′‐dimethyl]hexyl‐Δ8‐THC to 395±66.3 nM for 5′‐[N‐(4‐chlorophenyl)]‐1′,1′‐dimethyl‐carboxamido‐Δ8‐THC. 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. 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. 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. British Journal of Pharmacology (2001) 132, 525–535; doi:10.1038/sj.bjp.0703827