Novel 3‐substituted rimonabant analogues lack Δ9‐tetrahydrocannabinol‐like abuse‐related behavioural effects in mice

Abstract

Previous structure-activity relationship studies with analogues of the CB1 receptor antagonist rimonabant have demonstrated that a subset of these analogues with 3-substituent replacements of rimonabant's pyrazole core displayed cannabimimetic profiles seemingly independent of CB1 receptors. We sought to further evaluate these analogues in several behavioural models sensitive to detecting THC-like abuse liability. Selected analogues were tested in a battery of tests in mice to replicate previous findings. Cross-generalization tests were conducted in mice trained to discriminate either THC or O-6629 from vehicle. Rimonabant and its analogues were also evaluated in substitution and challenge tests. Finally, development of cross-tolerance between THC and O-6211 in the mouse test battery was assessed. O-6629 and O-6658 produced dose-dependent acute cannabimimetic activity in mice, but neither substituted for nor antagonized THC's discriminative stimulus. Cross-substitution was observed with O-6658 in mice discriminating O-6629, whereas rimonabant neither substituted for nor attenuated the O-6629 discriminative stimulus. THC and morphine did not generate O-6629-like responding. Cross-tolerance did not develop in mice repeatedly treated with THC when tested with O-6211 in the mouse test battery. While some overlap exists between the pharmacological profiles of THC and these 3-substituent rimonabant analogues, the effects are mediated by distinct neural targets. Notably, these analogues are unlikely to possess marijuana-like abuse liability in humans, but general abuse liability has not yet been determined. Efforts to determine the mechanism(s) of action of this seemingly unique class of compounds are underway.