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

1 The controversial nature of the CB1 receptor antagonist, SR141716A, in th e guinea-pig small intestine was investigated by comparing it with four ana logues of Delta(8)-tetrahydrocannabinol (Delta(8)- THC): O-1184, O-1238, O- 584 and O-1315. 2 These compounds (10-1000 nM) inhibited the electrically-evoked contractio ns with a rank order of potency of O-1235 > O-1184 > O-584 > O-1315. Log co ncentration-response curves for O-1238, O-1184 and O-1315 were significantl y 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. 3 Partial saturation of the triple bond in O-1184 to a cis double bond (O-1 238) increased its potency as an agonist (pEC(50) from 6.42 to 7.63) and as an antagonist of WIN55212-2, (pK(B), from 8.36 to 9.49). Substitution of t he terminal azide group by an ethyl group (O-584) or removal of the phenoli c hydroxyl group (O-1315) had no significant effect on the agonist or antag onist potency. None of these analogues increased the twitch response in a m anner resembling that of SR141716A. 4 O-1184 (10 and 100 nM) shifted the log concentration-response curve of WI N55212-2 for inhibition of the twitch responses to the right with pK(B) val ues of 8.29 and 8.38, respectively. 5 We conclude that these Delta(8)-THC analogues behave as partial agonists rather than silent antagonists at CB1 binding sites in this tissue. There w as no evidence of antagonism of endocannabinoids thus supporting the hypoth esis that, in this tissue, SR141716A is an inverse agonist of constitutivel y active CB1 receptors.