An Investigation Into The Structural Determinants Of Cannabinoid Receptor Ligand Efficacy

1 A number of side-chain analogues of Delta(8)-THC were tested in GTP gamma S binding assay in rat cerebellar membranes. O-1125, a saturated side-chain compound stimulated GTP gamma S binding with an E-max of 165.0%, and an EC50 Of 17.4 nM.2 O-1236, O-1237 and O-1238, three-enyl derivatives containing a cis carbon-carbon double bond in the side-chain, stimulated GTP gamma S binding, acting as partial agonists with E-max values ranging from 51.3-87.5% and EC50 values between 4.4 and 29.7 nM.3 The stimulatory effects of O-1125, O-1236, O-1237 and O-1238 on GTP gamma S binding were antagonized by the CBI receptor antagonist SR 141716A. The K-B Values obtained ranged from 0.11-0.21 mM, suggesting an action at CB1 receptors.4 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 GTP gamma S binding and were tested as potential cannabinoid receptor antagonists.5 Each -ynyl compound antagonized the stimulatory effects of four cannabinoid receptor agonists on GTP gamma S binding. The K-B values obtained, all found to be in the nanomolar range, did not differ between agonists or from cerebellar binding affinity.6 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.7 Furthermore, this study confirms the ability of the GTP gamma S 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.