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Structure‐activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens
Author(s) -
Ross Ruth A,
Gibson T Michael,
Brockie Heather C,
Leslie Mark,
Pashmi Ghazaleh,
Craib Susan J,
Di Marzo Vincenzo,
Pertwee Roger G
Publication year - 2001
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.0703850
Subject(s) - capsazepine , anandamide , chemistry , cannabinoid receptor , resiniferatoxin , cannabinoid , endocannabinoid system , pharmacology , vas deferens , receptor , trpv1 , medicine , endocrinology , agonist , biochemistry , biology , transient receptor potential channel
This study was directed at exploring the structure‐activity relationship for anandamide and certain of its analogues at the rat VR1 receptor in transfected cells and at investigating the relative extent to which anandamide interacts with CB 1 and vanilloid receptors in the mouse vas deferens. pK i values for displacement of [ 3 H]‐resiniferatoxin from membranes of rVR1 transfected CHO cells were significantly less for anandamide (5.78) than for its structural analogues N ‐(4‐hydroxyphenyl)‐arachidonylamide (AM404; 6.18) and N ‐(3‐methoxy‐4‐hydroxy)benzyl‐arachidonylamide (arvanil; 6.77). pEC 50 values for stimulating 45 Ca 2+ uptake into rVR1 transfected CHO cells were significantly less for anandamide (5.80) than for AM404 (6.32) or arvanil (9.29). Arvanil was also significantly more potent than capsaicin (pEC 50 =7.37), a compound with the same substituted benzyl polar head group as arvanil. In the mouse vas deferens, resiniferatoxin was 218 times more potent than capsaicin as an inhibitor of electrically‐evoked contractions. Both drugs were antagonized to a similar extent by capsazepine (pK B =6.93 and 7.18 respectively) but were not antagonized by SR141716A (1 μ M ). Anandamide was less susceptible than capsaicin to antagonism by capsazepine (pK B =6.02) and less susceptible to antagonism by SR141716A (pK B =8.66) than methanandamide (pK B =9.56). WIN55212 was antagonized by SR141716A (pK B =9.02) but not by capsazepine (10 μ M ). In conclusion, anandamide and certain of its analogues have affinity and efficacy at the rat VR1 receptor. In the mouse vas deferens, which seems to express vanilloid and CB 1 receptors, both receptor types appear to contribute to anandamide‐induced inhibition of evoked contractions.British Journal of Pharmacology (2001) 132 , 631–640; doi: 10.1038/sj.bjp.0703850