Cannabinoid Discrimination and Antagonism by CB1Neutral and Inverse Agonist Antagonists
| Autor: | Brian D. Kangas, Marcus S. Delatte, Ganesh A. Thakur, Kumara V. Subramanian, V. Kiran Vemuri, Alexandros Makriyannis, Jack Bergman, Spyridon P. Nikas, Vidyanand G. Shukla |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Agonist medicine.drug_class Pharmacology Ligands Partial agonist Discrimination Psychological Piperidines Receptor Cannabinoid CB1 Rimonabant medicine Animals Inverse agonist Dronabinol Cannabinoid Receptor Antagonists Saimiri Cannabinoid Receptor Agonists Dose-Response Relationship Drug Cannabinoids Chemistry musculoskeletal neural and ocular physiology Antagonist nervous system Behavioral Pharmacology Competitive antagonist cardiovascular system Pyrazoles Molecular Medicine Cannabinoid receptor antagonist lipids (amino acids peptides and proteins) psychological phenomena and processes medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 344:561-567 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.112.201962 |
| Popis: | Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB(1) neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB(1) inverse agonist SR141716A (rimonabant) and the CB(1) neutral antagonist AM4113 were compared for their ability to modify CB(1) receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB(1) full agonist AM4054. Results indicate that AM4054 serves as an effective CB(1) discriminative stimulus, with an onset and time course of action comparable with that of the CB(1) agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB(1) neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB(1) receptors. |
| Databáze: | OpenAIRE |
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