Comparison of novel cannabinoid partial agonists and SR141716A in the guinea‐pig small intestine

The controversial nature of the CB1 receptor antagonist, SR141716A, in the guinea‐pig small intestine was investigated by comparing it with four analogues of Δ8‐tetrahydrocannabinol (Δ8‐THC): O‐1184, O‐1238, O‐584 and O‐1315. These compounds (10–1000 nM) inhibited the electrically‐evoked contractions with a rank order of potency of O‐1238>O‐1184>O‐584>O‐1315. Log concentration‐response curves for O‐1238, O‐1184 and O‐1315 were significantly shifted to the right by SR141716A and the maxima were significantly less than that of the CB1 agonist, WIN55212‐2, an indication of partial agonism. Partial saturation of the triple bond in O‐1184 to a cis double bond (O‐1238) increased its potency as an agonist (pEC50 from 6.42 to 7.63) and as an antagonist of WIN55212‐2, (pKB, from 8.36 to 9.49). Substitution of the terminal azide group by an ethyl group (O‐584) or removal of the phenolic hydroxyl group (O‐1315) had no significant effect on the agonist or antagonist potency. None of these analogues increased the twitch response in a manner resembling that of SR141716A. O‐1184 (10 and 100 nM) shifted the log concentration‐response curve of WIN55212‐2 for inhibition of the twitch responses to the right with pKB values of 8.29 and 8.38, respectively. We conclude that these Δ8‐THC analogues behave as partial agonists rather than silent antagonists at CB1 binding sites in this tissue. There was no evidence of antagonism of endocannabinoids thus supporting the hypothesis that, in this tissue, SR141716A is an inverse agonist of constitutively active CB1 receptors. British Journal of Pharmacology (2000) 129, 645–652; doi:10.1038/sj.bjp.0703094