Suppression of food intake and food-reinforced behavior produced by the novel CB1 receptor antagonist/inverse agonist AM 1387
Suppression of food intake and food-reinforced behavior produced by the novel CB1 receptor antagonist/inverse agonist AM 1387
复制标题
DOI：
10.1016/j.pbb.2006.02.022
复制
发表时间：
2006-03-01
影响因子：
3.6
通讯作者：
Salamone, John D.
中科院分区：
文献类型：
--
作者：
McLaughlin, Peter J.;Qian, Liu;Salamone, John D.
大麻素CB 1受体拮抗剂/反向激动剂因其作为食欲抑制剂的潜在治疗效用而越来越受到认可。在目前的文件中，我们的特点AM 1387，这是一种新的CB 1拮抗剂的生化和行为的影响。AM 1387对CB 1的结合亲和力和选择性高于CB 2受体。此外，AM 1387降低GTP γ S（EC 50：22.82nM）并增加毛喉素刺激的cAMP（EC 50：274.6nM），与CB 1反向激动剂AM 251（GTP γ S EC 50：25.82nM; cAMP EC 50：363.8nM）一样，表明AM 1387在体外也具有反向激动剂性质。在大鼠的行为表征中，AM 1387在两个操作性时间表（固定比率1和5）上抑制杠杆按压食物。然后确定对固定比率5反应的影响的时间过程，发现半衰期（t（1/2）=4.87 h）比SR 141716 A短3倍，比AM 251短4倍。最后，发现AM 1387使用三种不同常量营养素组成和适口性的饮食抑制食物摄入。结论是AM 1387可能是用于检查CBI受体拮抗或反向激动对食物摄取的影响的有用工具。(c)2006年爱思唯尔公司All rights reserved.
Cannabinoid CB1 receptor antagonist/inverse agonists are becoming increasingly recognized for their potential therapeutic utility as appetite suppressants. In the current paper we characterize the biochemical and behavioral effects of AM 1387, which is a novel CB1 antagonist. AM 1387 exhibited binding affinity and selectivity for the CB1 over the CB2 receptor. Moreover, AM 1387 decreased GTP gamma S (EC50: 22.82nM) and increased forskolin-stimulated cAMP (EC50: 274.6nM), as did the CB1 inverse agonist AM 251 (GTP gamma S EC50: 25.82nM; cAMP EC50: 363.8nM), indicating that AM1387 also has inverse agonist properties in vitro. In the behavioral characterization in rats, AM 1387 suppressed lever pressing for food on two operant schedules (fixed-ratio 1 and 5). Timecourse of the effect on fixed-ratio 5 responding was then determined, and the half-life (t(1/2)=4.87 h) was found to be threefold shorter than what has been shown for SR 141716A, and fourfold shorter than AM 251. Finally, AM 1387 was found to suppress food intake using three diets of differing macronutrient composition and palatability. It was concluded that AM 1387 may be a useful tool for examining the effects of CBI receptor antagonism or inverse agonism on food intake. (c) 2006 Elsevier Inc. All rights reserved.