Addy Carol, Wright Hamish, Van Laere Koen, Gantz Ira, Erondu Ngozi, Musser Bret J, Lu Kaifeng, Yuan Jinyu, Sanabria-Bohórquez Sandra M, Stoch Aubrey, Stevens Cathy, Fong Tung M, De Lepeleire Inge, Cilissen Caroline, Cote Josee, Rosko Kim, Gendrano Isaias N, Nguyen Allison Martin, Gumbiner Barry, Rothenberg Paul, de Hoon Jan, Bormans Guy, Depré Marleen, Eng Wai-si, Ravussin Eric, Klein Samuel, Blundell John, Herman Gary A, Burns H Donald, Hargreaves Richard J, Wagner John, Gottesdiener Keith, Amatruda John M, Heymsfield Steven B
Merck Research Laboratories, Boston, MA 02115, USA.
Cell Metab. 2008 Jan;7(1):68-78. doi: 10.1016/j.cmet.2007.11.012.
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.
大麻素1型受体（CB1R）反向激动剂正逐渐成为一种潜在的肥胖治疗药物。然而，这些药物调节人体能量平衡的生理机制尚未完全阐明。在此，我们描述了一项关于新型结构的非环状CB1R反向激动剂——替拉那班的全面临床研究。使用选择性CB1R示踪剂[（18）F]MK-9470的正电子发射断层扫描成像证实了中枢神经系统受体占有率水平（约10%-40%）与动物能量平衡/体重减轻效应相关。在一项为期12周的减肥研究中，在整个评估剂量范围（0.5、2、4和6毫克，每日一次）内，与安慰剂相比，替拉那班在肥胖受试者中诱导出具有统计学意义的体重减轻（p<0.001）。替拉那班治疗与临床不良事件的剂量相关发生率增加有关，包括轻度至中度胃肠道和精神方面的影响。作用机制研究表明，替拉那班与CB1R结合通过减少食物摄入量、增加能量消耗和脂肪氧化导致体重减轻。
