| Novel 3-substituted rimonabant analogs lack Δ(9) -tetrahydrocannabinol-like abuse-related behavioral effects in mice. | |
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MedLine Citation:
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PMID: 23297801 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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D M Walentiny; R E Vann; A Mahadevan; R Kottani; R Gujjar; J L Wiley |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-9 |
Journal Detail:
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Title: British journal of pharmacology Volume: - ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society. |
Affiliation:
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Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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