title: Novel 3-substituted rimonabant analogues lack Δ(9) -tetrahydrocannabinol-like abuse-related behavioural effects in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA. walentinydm@vcu.edu
authors.forename: Dm
authors.initials: D
authors.lastname: Walentiny
authors.forename: Re
authors.initials: R
authors.lastname: Vann
authors.forename: A
authors.initials: A
authors.lastname: Mahadevan
authors.forename: R
authors.initials: R
authors.lastname: Kottani
authors.forename: R
authors.initials: R
authors.lastname: Gujjar
authors.forename: Jl
authors.initials: J
authors.lastname: Wiley
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology*; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D010080:Oxazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000077285:Rimonabant; D013329:Structure-Activity Relationship
chemical_list: D063387:Cannabinoid Receptor Antagonists; C000591335:O-6629; C000591336:O-6658; D010080:Oxazoles; D010880:Piperidines; D011720:Pyrazoles; D009020:Morphine; D013759:Dronabinol; D000077285:Rimonabant