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

被引：182

作者：

Addy, Carol ^{[2
]}

Wright, Hamish ^{[1
]}

Van Laere, Koen ^{[3
,4
]}

Gantz, Ira ^{[1
]}

Erondu, Ngozi ^{[1
]}

Musser, Bret J. ^{[1
]}

Lu, Kaifeng ^{[1
]}

Yuan, Jinyu ^{[1
]}

Sanabria-Bohorquez, Sandra M. ^{[5
]}

Stoch, Aubrey ^{[1
]}

Stevens, Cathy ^{[1
]}

Fong, Tung M. ^{[1
]}

De Lepeleire, Inge ^{[6
]}

Cilissen, Caroline ^{[6
]}

Cote, Josee ^{[1
]}

Rosko, Kim ^{[1
]}

Gendrano, Isaias N., III ^{[1
]}

Nguyen, Allison Martin ^{[7
]}

Gumbiner, Barry ^{[1
]}

Rothenberg, Paul ^{[1
]}

de Hoon, Jan ^{[8
]}

Bormans, Guy ^{[1
,3
,4
]}

Depre, Marleen ^{[8
]}

Eng, Wai-Si

Ravussin, Eric ^{[9
]}

Klein, Samuel ^{[10
]}

Blundell, John ^{[11
]}

Herman, Gary A.

Burns, H. Donald ^{[5
]}

Hargreaves, Richard J. ^{[5
]}

Wagner, John ^{[1
]}

Gottesdiener, Keith ^{[1
]}

Amatruda, John M.

Heymsfield, Steven B. ^{[1
]}

机构：

[1] Merck Res Labs, Boston, MA 02115 USA

[2] Merck Res Labs, Rahway, NJ 07065 USA

[3] Univ Hosp, Div Nucl Med, B-3000 Louvain, Belgium

[4] Katholieke Univ Leuven, B-3000 Louvain, Belgium

[5] Merck Res Labs, West Point, PA 19486 USA

[6] MSD Europe Inc, B-1200 Brussels, Belgium

[7] Merck Res Labs, N Wales, PA 19454 USA

[8] Katholieke Univ Leuven, Ctr Clin Pharmacol, B-1200 Brussels, Belgium

[9] Louisiana State Univ, Pennington Biomed Res Ctr, Div Hlth & Performance Enhancement, Baton Rouge, LA 70808 USA

[10] Washington Univ, Sch Med, Ctr Human Nutr, St Louis, MO 63156 USA

[11] Univ Leeds, Inst Psychol Sci, Leeds LS2 9JT, W Yorkshire, England

来源：

CELL METABOLISM | 2008年 / 7卷 / 01期

关键词：

D O I：

10.1016/j.cmet.2007.11.012

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 [细胞生物学]; 090102 [作物遗传育种];

摘要：

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 CB1 R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [F-18]MK-9470 confirmed central nervous system receptor occupancy levels (similar to 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.

引用

页码：68 / 78

页数：11

共 59 条

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