Development of Functionally Selective, Small Molecule Agonists at Kappa Opioid Receptors
Development of Functionally Selective, Small Molecule Agonists at Kappa Opioid Receptors
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DOI：
10.1074/jbc.m113.504381
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发表时间：
2013-12-20
影响因子：
4.8
通讯作者：
Bohn, Laura M.
中科院分区：
文献类型：
--
作者：
Zhou, Lei;Lovell, Kimberly M.;Bohn, Laura M.
背景：Kappa阿片受体(KOR)信号可能通过G蛋白产生抗伤害性感觉，或通过arrestin途径产生烦躁不安。结果：两种高选择性的脑穿透性激动剂支架使KOR信号偏向G蛋白偶联，并在小鼠中产生抗伤害效应。结论：描述了一类通过G蛋白偏向KOR信号的一流小分子激动剂。意义：功能选择性KOR激动剂现在可以用于活体。kappa阿片受体(KOR)在中枢神经系统中广泛表达，可以作为一种手段来调节疼痛感知、应激反应和情感奖励状态。因此，KOR已成为治疗疼痛、抑郁和药物成瘾的重要药物发现目标。KOR的激动剂可以促进G蛋白偶联、抑制蛋白2的募集以及多种下游信号通路，包括ERK1/2 MAPK的激活。已有研究表明，KOR激活的生理效应来自不同的信号级联反应，其中镇痛作用是G蛋白介导的，烦躁不安是通过arrestin2募集介导的。与KOR激活相关的焦虑症限制了KOR激动剂作为镇痛剂的治疗潜力；因此，开发偏向G蛋白偶联而不是抑制蛋白2募集的KOR激动剂可能是有益的。在这里，我们描述了两类有偏见的KOR激动剂，它们有效地激活了G蛋白偶联，但微弱地招募了抑制蛋白2。这些有效的和功能选择性的小分子化合物可能被证明是在体内提炼KOR定向信号治疗潜力的有用工具。
Background: Kappa opioid receptor (KOR) signaling may produce antinociception through G protein or dysphoria through arrestin pathways. Results: Two highly selective, brain penetrant agonist scaffolds bias KOR signaling toward G protein coupling and produce antinociception in mice. Conclusion: Described are first-in-class small molecule agonists that bias KOR signaling through G proteins. Significance: Functionally selective KOR agonists can now be used in vivo.The kappa opioid receptor (KOR) is widely expressed in the CNS and can serve as a means to modulate pain perception, stress responses, and affective reward states. Therefore, the KOR has become a prominent drug discovery target toward treating pain, depression, and drug addiction. Agonists at KOR can promote G protein coupling and arrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation. It has been suggested that the physiological effects of KOR activation result from different signaling cascades, with analgesia being G protein-mediated and dysphoria being mediated through arrestin2 recruitment. Dysphoria associated with KOR activation limits the therapeutic potential in the use of KOR agonists as analgesics; therefore, it may be beneficial to develop KOR agonists that are biased toward G protein coupling and away from arrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activate G protein coupling but weakly recruit arrestin2. These potent and functionally selective small molecule compounds may prove to be useful tools for refining the therapeutic potential of KOR-directed signaling in vivo.