The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake.

Abstract

Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.

• Authors: Carol Addy, Hamish Wright, Koen Van Laere, Ira Gantz, Ngozi Erondu, Bret J Musser, Kaifeng Lu, Jinyu Yuan, Sandra M Sanabria-Bohórquez, Aubrey Stoch, Cathy Stevens, Tung M Fong, Inge De Lepeleire, Caroline Cilissen, Josee Cote, Kim Rosko, Isaias N Gendrano 3rd, Allison Martin Nguyen, Barry Gumbiner, Paul Rothenberg, Jan de Hoon, Guy Bormans, Marleen Depré, Wai-si Eng, Eric Ravussin, Samuel Klein, John Blundell, Gary A Herman, H Donald Burns, Richard J Hargreaves, John Wagner, Keith Gottesdiener, John M Amatruda, Steven B Heymsfield
• Journal: Cell metabolism (Cell Metab) Vol. 7 Issue 1 Pg. 68-78 (Jan 2008) ISSN: 1550-4131 [Print] United States
• PMID: 18177726 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Fats
• Pyridines
• Receptor, Cannabinoid, CB1
• N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

Topics

• Adult
• Aged
• Amides (pharmacology, therapeutic use)
• Brain (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Energy Intake (drug effects)
• Energy Metabolism (drug effects)
• Fats (metabolism)
• Humans
• Middle Aged
• Positron-Emission Tomography
• Pyridines (pharmacology, therapeutic use)
• Receptor, Cannabinoid, CB1 (agonists)
• Weight Loss (drug effects)