An investigation into the structural determinants of cannabinoid receptor ligand efficacy

A number of side‐chain analogues of Δ8‐THC were tested in GTPγS binding assay in rat cerebellar membranes. O‐1125, a saturated side‐chain compound stimulated GTPγS binding with an Emax of 165.0%, and an EC50 of 17.4 nM. O‐1236, O‐1237 and O‐1238, three‐enyl derivatives containing a cis carbon‐carbon double bond in the side‐chain, stimulated GTPγS binding, acting as partial agonists with Emax values ranging from 51.3–87.5% and EC50 values between 4.4 and 29.7 nM. The stimulatory effects of O‐1125, O‐1236, O‐1237 and O‐1238 on GTPγS binding were antagonized by the CB1 receptor antagonist SR 141716A. The KB values obtained ranged from 0.11–0.21 mM, suggesting an action at CB1 receptors. Five‐ynyl derivatives (O‐584, O‐806, O‐823, O‐1176 and O‐1184), each containing a carbon‐carbon triple bond in the side‐chain, did not stimulate GTPγS binding and were tested as potential cannabinoid receptor antagonists. Each ‐ynyl compound antagonized the stimulatory effects of four cannabinoid receptor agonists on GTPγS binding. The KB values obtained, all found to be in the nanomolar range, did not differ between agonists or from cerebellar binding affinity. In conclusion, alterations of the side‐chain of the classical cannabinoid structure may exert a large influence on affinity and efficacy at the CB1 receptor. Furthermore, this study confirms the ability of the GTPγS binding assay to assess discrete differences in ligand efficacies which potentially may not be observed using alternative functional assays, thus providing a unique tool for the assessment of the molecular mechanisms underlying ligand efficacies. British Journal of Pharmacology (1999) 126, 1575–1584; doi:10.1038/sj.bjp.0702469