Regulation of Ingestive Behaviors in the Rat by GSK1521498, a Novel μ-Opioid Receptor-Selective Inverse Agonist
Regulation of Ingestive Behaviors in the Rat by GSK1521498, a Novel μ-Opioid Receptor-Selective Inverse Agonist
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DOI：
10.1124/jpet.111.180943
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发表时间：
2011-10-01
影响因子：
3.5
通讯作者：
Hommel, Jonathan D.
中科院分区：
文献类型：
--
作者：
Ignar, Diane M.;Goetz, Aaron S.;Hommel, Jonathan D.
μ-阿片样物质受体（莫尔）激动作用主要通过调节食物的奖励性质来诱导可口的食物消耗。N-{[3，5-二氟-3 '-（1H-1，2，4-三唑-3-基）-4-联苯基]甲基}-2，3-二氢-1H-茚-2-胺（GSK 1521498）是一种新的阿片受体反向激动剂，基于体外亲和力测定，其对人或大鼠莫尔的选择性分别大于10倍或50倍，与κ-阿片受体（KOR）和δ-阿片受体（DOR）相比。同样，通过放射自显影术在Long Evans大鼠经口给药的脑切片中观察到与KOR和DOR相比优先的莫尔占据。GSK 1521498抑制了瘦型和饮食诱导肥胖（DIO）Long Evans大鼠的标准或可口食物的夜间摄食量。在饲喂可口食物的瘦大鼠中，剂量-反应关系和疗效的时间过程均与mu受体占用率和药物的血浆浓度曲线相关。长期经口给予GSK 1521498诱导DIO大鼠体重减轻，包括脂肪量减少。体重减轻相当于摄食量的累积减少;因此，GSK 1521498对体重的影响与摄食量抑制相关。GSK 1521498抑制了瘦大鼠对含蔗糖溶液的偏好。在也使用瘦大鼠的操作性反应模型中，GSK 1521498降低了可口食物奖励的强化功效并增强了饱腹感。总之，GSK 1521498是一种有效的MOR选择性反向激动剂，可调节摄入的享乐方面，因此，可代表肥胖和暴食症的药理学治疗。
mu-Opioid receptor (MOR) agonism induces palatable food consumption principally through modulation of the rewarding properties of food. N-{[3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) is a novel opioid receptor inverse agonist that, on the basis of in vitro affinity assays, is greater than 10- or 50-fold selective for human or rat MOR, respectively, compared with kappa-opioid receptors (KOR) and delta-opioid receptors (DOR). Likewise, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and diet-induced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with mu receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats, which comprised fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption; thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates the hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders.