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An investigation into the structural determinants of cannabinoid receptor ligand efficacy
Author(s) -
Griffin Graeme,
Wray Emma J,
Rorrer William K,
Crocker Peter J,
Ryan William J,
Saha Bijali,
Razdan Raj K,
Martin Billy R,
Abood Mary E
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702469
Subject(s) - gtp' , cannabinoid receptor agonists , cannabinoid receptor , chemistry , cannabinoid , receptor , stereochemistry , antagonist , g protein , side chain , cannabinoid receptor antagonist , biochemistry , enzyme , organic chemistry , polymer
A number of side‐chain analogues of Δ 8 ‐THC were tested in GTPγS binding assay in rat cerebellar membranes. O‐1125, a saturated side‐chain compound stimulated GTPγS binding with an E max of 165.0%, and an EC 50 of 17.4 n M . 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 E max values ranging from 51.3–87.5% and EC 50 values between 4.4 and 29.7 n M . The stimulatory effects of O‐1125, O‐1236, O‐1237 and O‐1238 on GTPγS binding were antagonized by the CB 1 receptor antagonist SR 141716A. The K B values obtained ranged from 0.11–0.21 m M , suggesting an action at CB 1 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 K B 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 CB 1 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