Document Detail


Novel 3-substituted rimonabant analogs lack Δ(9) -tetrahydrocannabinol-like abuse-related behavioral effects in mice.
MedLine Citation:
PMID:  23297801     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Previous structure activity relationship studies with analogs of the CB(1) receptor antagonist rimonabant have demonstrated that a subset of these analogs with 3-substituent replacements of rimonabant's pyrazole core displayed cannabimimetic profiles seemingly independent of CB(1) receptors. We sought to further evaluate these analogs in several behavioral models sensitive to detecting THC-like abuse liability. EXPERIMENTAL APPROACH: Selected analogs 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 analogs 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. KEY 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 AND IMPLICATIONS: While some overlap exists between the pharmacological profiles of THC and these 3-substituent rimonabant analogs, the effects are mediated by distinct neural targets. Notably, these analogs 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:
D M Walentiny; R E Vann; A Mahadevan; R Kottani; R Gujjar; J L Wiley
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-9
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.
Affiliation:
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
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