2. Academic Validation
  3. Discovery of β-arrestin-biased β2-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives

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

  • Acta Pharmacol Sin. 2019 Aug;40(8):1095-1105. doi: 10.1038/s41401-018-0200-x.
Anthony Yiu-Ho Woo # 1 2,  Xin-Yue Ge # 3 4,  Li Pan 3 4,  Gang Xing 3 4,  Yong-Mei Mo 3 4,  Rui-Juan Xing 3 4 5,  Xiao-Ran Li 1,  Yu-Yang Zhang 1,  Irving W Wainer 6 7,  Mao-Sheng Cheng 8 9,  Rui-Ping Xiao 10 11 12
Affiliations

Affiliations

  • 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 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 Department of Medicinal Chemistry, Shenyang Pharmaceutical University, Shenyang, 110016, China. [email protected].
  • 9 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. [email protected].
  • 10 State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing, 100871, China. [email protected].
  • 11 Centers for Life Sciences, Peking University, Beijing, 100871, China. [email protected].
  • 12 Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China. [email protected].
  • # Contributed equally.
PMID: 30643208 DOI: 10.1038/s41401-018-0200-x
Abstract

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

asthma; biased agonism; cAMP; fenoterol; heart failure; salmeterol; β-arrestin; β2-adrenoceptor agonists.

Figures
Products