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Identification and Characterization of the First Selective Y4 Receptor Positive Allosteric Modulator
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00976 Mario Schubert 1 , Jan Stichel 1 , Yu Du 2 , Iain R. Tough 3 , Gregory Sliwoski 4 , Jens Meiler 4, 5 , Helen M. Cox 3 , C. David Weaver 2, 5 , Annette G. Beck-Sickinger 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00976 Mario Schubert 1 , Jan Stichel 1 , Yu Du 2 , Iain R. Tough 3 , Gregory Sliwoski 4 , Jens Meiler 4, 5 , Helen M. Cox 3 , C. David Weaver 2, 5 , Annette G. Beck-Sickinger 1
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The human Y4 receptor (Y4R) and its cognate ligand, pancreatic polypeptide (PP), are involved in the regulation of energy expenditure, satiety, and food intake. This system represents a potential target for the treatment of metabolic diseases and has been extensively investigated and validated in vivo. Here, we present the compound tBPC (tert-butylphenoxycyclohexanol), a novel and selective Y4R positive allosteric modulator that potentiates Y4R activation in G-protein signaling and arrestin3 recruitment experiments. The compound has no effect on the binding of the orthosteric ligands, implying its allosteric mode of action at the Y4R and evidence for a purely efficacy-driven positive allosteric modulation. Finally, the ability of tBPC to selectively potentiate Y4R agonism initiated by PP was confirmed in mouse descending colon mucosa preparations expressing native Y4R, demonstrating Y4R positive allosteric modulation in vitro.
中文翻译：
第一个选择性Y 4受体正变构调节剂的鉴定与表征
人Y 4受体（Y 4 R）及其同源配体胰多肽（PP）参与能量消耗，饱腹感和食物摄入的调节。该系统代表了治疗代谢疾病的潜在靶标，并且已经在体内进行了广泛的研究和验证。在这里，我们介绍化合物tBPC（叔丁基苯氧基环己醇），一种新型的和选择性的Y 4 R阳性变构调节剂，可增强G蛋白信号转导和restingin3募集实验中的Y 4 R活化。该化合物对正构配体的结合没有影响，暗示其在Y 4处的变构作用方式R和纯功效驱动的正变构调制的证据。最后，在表达天然Y 4 R的小鼠降结肠粘膜制剂中证实了tBPC选择性增强PP启动的Y 4 R激动的能力，证明了体外的Y 4 R正构构调节。
更新日期：2017-08-28
中文翻译：
第一个选择性Y 4受体正变构调节剂的鉴定与表征
人Y 4受体（Y 4 R）及其同源配体胰多肽（PP）参与能量消耗，饱腹感和食物摄入的调节。该系统代表了治疗代谢疾病的潜在靶标，并且已经在体内进行了广泛的研究和验证。在这里，我们介绍化合物tBPC（叔丁基苯氧基环己醇），一种新型的和选择性的Y 4 R阳性变构调节剂，可增强G蛋白信号转导和restingin3募集实验中的Y 4 R活化。该化合物对正构配体的结合没有影响，暗示其在Y 4处的变构作用方式R和纯功效驱动的正变构调制的证据。最后，在表达天然Y 4 R的小鼠降结肠粘膜制剂中证实了tBPC选择性增强PP启动的Y 4 R激动的能力，证明了体外的Y 4 R正构构调节。
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