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β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors.
Cell ( IF 45.5 ) Pub Date : 2020-05-28 , DOI: 10.1016/j.cell.2020.04.053
Lauren M Slosky 1 , Yushi Bai 1 , Krisztian Toth 2 , Caroline Ray 1 , Lauren K Rochelle 1 , Alexandra Badea 3 , Rahul Chandrasekhar 1 , Vladimir M Pogorelov 4 , Dennis M Abraham 5 , Namratha Atluri 1 , Satyamaheshwar Peddibhotla 6 , Michael P Hedrick 6 , Paul Hershberger 6 , Patrick Maloney 6 , Hong Yuan 7 , Zibo Li 8 , William C Wetsel 9 , Anthony B Pinkerton 6 , Lawrence S Barak 1 , Marc G Caron 10
Affiliation  

Small molecule neurotensin receptor 1 (NTSR1) agonists have been pursued for more than 40 years as potential therapeutics for psychiatric disorders, including drug addiction. Clinical development of NTSR1 agonists has, however, been precluded by their severe side effects. NTSR1, a G protein-coupled receptor (GPCR), signals through the canonical activation of G proteins and engages β-arrestins to mediate distinct cellular signaling events. Here, we characterize the allosteric NTSR1 modulator SBI-553. This small molecule not only acts as a β-arrestin-biased agonist but also extends profound β-arrestin bias to the endogenous ligand by selectively antagonizing G protein signaling. SBI-553 shows efficacy in animal models of psychostimulant abuse, including cocaine self-administration, without the side effects characteristic of balanced NTSR1 agonism. These findings indicate that NTSR1 G protein and β-arrestin activation produce discrete and separable physiological effects, thus providing a strategy to develop safer GPCR-targeting therapeutics with more directed pharmacological action.



中文翻译:


NTSR1 的 β-Arrestin 偏向变构调节剂选择性减弱成瘾行为。



小分子神经降压素受体 1 (NTSR1) 激动剂作为治疗精神疾病(包括毒瘾)的潜在疗法已被研究了 40 多年。然而,NTSR1 激动剂的临床开发因其严重的副作用而受到阻碍。 NTSR1 是一种 G 蛋白偶联受体 (GPCR),通过 G 蛋白的典型激活发出信号,并与 β-抑制蛋白结合来介导不同的细胞信号转导事件。在这里,我们表征了变构 NTSR1 调制器 SBI-553。这种小分子不仅充当 β-arrestin 偏向激动剂,而且还通过选择性拮抗 G 蛋白信号传导,将深刻的 β-arrestin 偏向延伸至内源配体。 SBI-553 在精神兴奋剂滥用(包括可卡因自我给药)的动物模型中显示出功效,且没有平衡 NTSR1 激动作用所特有的副作用。这些发现表明 NTSR1 G 蛋白和 β-arrestin 激活产生离散且可分离的生理效应,从而提供了开发更安全、具有更定向药理作用的 GPCR 靶向疗法的策略。

更新日期:2020-05-28
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