A New Series of G s ‐ and β‐Arrestin‐biased β 2 ‐Adrenoceptor Agonists
A New Series of G s ‐ and β‐Arrestin‐biased β 2 ‐Adrenoceptor Agonists
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新系列 G s – 和 β – Arrestin – 偏向 β 2 – 肾上腺素受体激动剂
DOI：
10.1096/fasebj.2019.33.1_supplement.lb379
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Rui-Ping Xiao
中科院分区：
文献类型：
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作者：
Anthony Yiu-Ho Woo;Xinyue Ge;Li Pan;Gang Xing;Yongmei Mo;Ruijuan Xing;Xiaoran Li;Yuyang Zhang;Irving W. Wainer;Maosheng Cheng;Rui-Ping Xiao
β-抑制蛋白参与激活的 G 蛋白偶联受体 (GPCR) 的脱敏和信号转导。已经描述了偏向配体在激活单个 GPCR 下游的不同 G 蛋白依赖性和 β-抑制蛋白依赖性信号方面具有不同功效。在这里，我们报告了沿着 β2-肾上腺素受体激动剂药物发现项目开发的化合物的激动剂偏倚特征。获得或合成了化合物，包括非诺特罗、2-氨基-1-苯基乙醇和2-氨基-2-苯基乙醇的衍生物，并在表达β2-肾上腺素受体的细胞中测定了它们对心肌细胞收缩性、cAMP合成和β-抑制蛋白募集的影响。通过操作模型分析 Gs 与 β-arrestin 偏差。通过对百日咳毒素（一种 Gidisruptor）的敏感性来研究 Gs 与 Gs/Gibias。三种具有 5-(1-氨基-2-羟乙基)-8-羟基喹啉-2(1H)-one 核心结构的化合物被鉴定为偏向 β-抑制素的 β2-肾上腺素受体激动剂。这些发现将有助于开发治疗心力衰竭和哮喘的新药。支持或资助信息这项工作得到了中华人民共和国科学技术部国家重点研发计划[2018YFA0507603]、国家科技重大专项[2013ZX09507001‐001002]的支持。 2013ZX09301305-001、2013ZX09508104、2018ZX09739009]、国家基础研究计划项目[2012CB518000]、国家自然科学基金项目[81673355、81872752、31521062、 81630008, 81790621]，北京市科委[Z171100000417006]，美国NIH校内研究项目。本文摘要来自实验生物学2019年会议。 FASEB 期刊上没有发表与此摘要相关的全文文章。
β‐Arrestins are implicated in desensitization of activated G protein‐coupled receptors (GPCRs) and transduction of signals in their own right. Biased ligands possessing different efficacies in activating different G protein‐dependent and β‐arrestin‐dependent signals downstream of a single GPCR have been described. Here, we report the characterization of agonist bias for compounds developed along a drug discovery project of β2‐adrenoceptor agonists. Compounds, including derivatives of fenoterol, 2‐amino‐1‐phenylethanol and 2‐amino‐2‐phenylethanol, were obtained or synthesized and their effects on cardiomyocyte contractility, cAMP synthesis and β‐arrestin recruitment were determined in β2‐adrenoceptor‐expressing cells. Gsversus β‐arrestin bias were analyzed by the operational model. Gsversus Gs/Gibias were studied by means of sensitivity towards pertussis toxin, a Gidisruptor. Three compounds with a core structure of 5‐(1‐amino‐2‐hydroxyethyl)‐8‐hydroxyquinolin‐2(1H)‐one were identified as β‐arrestin‐biased β2‐adrenoceptor agonists. These findings would facilitate the development of novel drugs for the treatment of heart failure and asthma.Support or Funding InformationThis work was supported by the Ministry of Science and Technology of the People's Republic of China under the National Key Research and Development Program of China [2018YFA0507603], the National Science and Technology Major Project [2013ZX09507001‐001002, 2013ZX09301305‐001, 2013ZX09508104, 2018ZX09739009], the National Basic Research Program [2012CB518000], the National Natural Science Foundation of China [81673355, 81872752, 31521062, 81630008, 81790621], Beijing Municipal Science & Technology Commission [Z171100000417006], and the intramural research program of the NIH, USA.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published inThe FASEB Journal.