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-chai n compound stimulated GTP gamma S binding with an E-max of 165.0%, and an E C50 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, acti ng as partial agonists with E-max values ranging from 51.3-87.5% and EC50 v alues 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 r eceptors. 4 Five-ynyl derivatives (O-584, O-806, O-823, O-1176 and O-1184), each cont aining a carbon-carbon triple bond in the side-chain, did not stimulate GTP gamma S binding and were tested as potential cannabinoid receptor antagoni sts. 5 Each -ynyl compound antagonized the stimulatory effects of four cannabino id receptor agonists on GTP gamma S binding. The K-B values obtained, all f ound 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 a ssay to assess discrete differences in ligand efficacies which potentially may not be observed using alternative functional assays, thus providing a u nique tool for the assessment of the molecular mechanisms underlying ligand efficacies.