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-tetrahydroc annabinol (Delta (8)-THC) in rat cerebellar membrane preparations were test ed. 2 The affinities of each compound for the CB1 receptor were compared by the ir respective abilities to displace [H-3]-SR141716A and their efficacies co mpared by stimulation of [S-35]-GTP gammaS binding. 3 It was found that the affinities varied from 0.19+/-0.03 nhl for 3-norpen tyl-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 l ow efficacy exhibited to acetylenic compounds such as 1'-heptyn-Delta (8)-T HC and 4'-octyn-Delta (8)-THC to higher efficacy compounds such as 5'-(4-cy anophenoxy)-1',1'-dimethyl-Delta (8)-THC and 5'-[N-(4-aminosulphonylphenyl) ]-1',1' dimethyl-carboxamido Delta (8)-THC. All agonist activities were ant agonized 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. Additio nally, the positioning of electrostatic moieties. such as cyano groups. wit hin 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 mo ieties in the side-chain and also how alteration of the side-chain's flexib ility may differentially affect a CB1 cannabinoid receptor ligand's affinit y and efficacy.