Discovery of β-arrestin-biased β2-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives

Anthony Yiu-Ho Woo1,2, Xin-yue Ge3,4, Li Pan3,4, Gang Xing3,4, Yong-mei Mo3,4, Rui-juan Xing3,4,5, Xiao-ran Li1, Yu-yang Zhang1, Irving W. Wainer6,7, Mao-sheng Cheng3,4, Rui-ping Xiao2,8,9
1 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China
2 State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing 100871, China
3 Department of Medicinal Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, China
4 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
5 resent address: School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China
6 Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD 21224, USA
7 Mitchell Woods Pharmaceuticals, LLC, Shelton, CT 06484, USA
8 Centers for Life Sciences, Peking University, Beijing 100871, China
9 Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China
Correspondence to: Anthony Yiu-Ho Woo:, Mao-sheng Cheng:, Rui-ping Xiao:,
DOI: 10.1038/s41401-018-0200-x
Received: 5 July 2018
Accepted: 1 January 1970
Advance online: 14 January 2019


β-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). β-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the β-arrestin-dependent signals downstream of a single GPCR have emerged, which can be used to selectively modulate GPCR signal transduction in such a way that desirable signals are enhanced to produce therapeutic effects while undesirable signals of the same GPCR are suppressed to avoid side effects. In the present study, we evaluated agonist bias for compounds developed along a drug discovery project of β2-adrenoceptor agonists. About 150 compounds, including derivatives of fenoterol, 2-amino-1-phenylethanol and 2-amino-2-phenylethanol, were obtained or synthesized, and initially screened for their β-adrenoceptor-mediated activities in the guinea pig tracheal smooth muscle relaxation assay or the cardiomyocyte contractility assay. Nineteen bioactive compounds were further assessed using both the HTRF cAMP assay and the PathHunter β-arrestin assay. Their concentration-response data in stimulating cAMP synthesis and β-arrestin recruitment were applied to the Black–Leff operational model for ligand bias quantitation. As a result, three compounds (L-2, L-4, and L-12) with the core structure of 5-(1-amino-2-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one were identified as a new series of β-arrestin-biased β2-adrenoceptor agonists, whereas salmeterol was found to be Gs-biased. These findings would facilitate the development of novel drugs for the treatment of both heart failure and asthma.
Keywords: β2-adrenoceptor agonists; cAMP; β-arrestin; biased agonism; fenoterol; salmeterol; heart failure; asthma

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