PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats
PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats
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DOI：
10.1038/sj.bjp.0707347
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发表时间：
2007-11-01
影响因子：
7.3
通讯作者：
In, P. Wong Kai
中科院分区：
文献类型：
--
作者：
Horswill, J. G.;Bali, U.;In, P. Wong Kai
背景和目的：利莫那班（Acomplia（TM），SR 141716 A）是一种大麻素CB 1受体反向激动剂，最近已被批准用于治疗肥胖症。然而，人们担心它的副作用。开发具有不同药理学机制的CB 1拮抗剂可能会导致更安全的替代方案。为此，我们筛选了一个专有的小分子文库，并发现了一类新的CB 1受体变构拮抗剂。在此，我们已经确定了一个优化的原型分子，PSNCBAM-1，和它的hypophagic在vivo.Experimental方法的影响：一个CB 1酵母报告分析被用作初步筛选。PSNCBAM-1还在[ S-35]-GTP γ S、cAMP和放射性配体结合试验中进行了表征。关键结果：在CB 1受体酵母报告基因分析中，PSNCBAM-1阻断了由激动剂如CP 55、940、WIN 55212 -2、花生四烯酸酰胺（AEA）或2-花生四烯酸甘油（2-AG）诱导的效应。在[S-35]-GTPgS结合和cAMP测定中证实了PSNCBAM-1的拮抗剂特征，并且通过Schild分析显示其是非竞争性的。PSNCBAM-1不影响CB 2受体。在放射性配体结合试验中，PSNCBAM-1增加了[H-3] CP 55，940的结合，尽管它具有拮抗剂作用。在急性大鼠喂养模型中，PSNCBAM-1减少摄食量和体重。结论和影响：PSNCBAM-1发挥其作用，通过选择性别构调节CB 1受体。在大鼠中诱导的对食物摄入和体重的急性效应提供了关于变构CB 1受体拮抗剂的体内活性的首次报告。
Background and purpose: Rimonabant ( Acomplia (TM), SR141716A), a cannabinoid CB1 receptor inverse agonist, has recently been approved for the treatment of obesity. There are, however, concerns regarding its side effect profile. Developing a CB1 antagonist with a different pharmacological mechanism may lead to a safer alternative. To this end we have screened a proprietary small molecule library and have discovered a novel class of allosteric antagonist at CB1 receptors. Herein, we have characterized an optimized prototypical molecule, PSNCBAM-1, and its hypophagic effects in vivo.Experimental approach: A CB1 yeast reporter assay was used as a primary screen. PSNCBAM-1 was additionally characterized in [ S-35]-GTP gamma S, cAMP and radioligand binding assays. An acute rat feeding model was used to evaluate its effects on food intake and body weight in vivo.Key results: In CB1 receptor yeast reporter assays, PSNCBAM-1 blocked the effects induced by agonists such as CP55,940, WIN55212-2, anandamide (AEA) or 2-arachidonoyl glycerol (2-AG). The antagonist characteristics of PSNCBAM-1 were confirmed in [S-35]-GTPgS binding and cAMP assays and was shown to be non-competitive by Schild analyses. PSNCBAM-1 did not affect CB2 receptors. In radioligand binding assays, PSNCBAM-1 increased the binding of [H-3] CP55,940 despite its antagonist effects. In an acute rat feeding model, PSNCBAM-1 decreased food intake and body weight.Conclusions and implications: PSNCBAM-1 exerted its effects through selective allosteric modulation of the CB1 receptor. The acute effects on food intake and body weight induced in rats provide a first report of in vivo activity for an allosteric CB1 receptor antagonist.