Dataset Information

Discovery of ?-arrestin-biased ?₂-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.

ABSTRACT: ?-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). ?-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the ?-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 ?₂-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 ?-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 ?-arrestin assay. Their concentration-response data in stimulating cAMP synthesis and ?-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 ?-arrestin-biased ?₂-adrenoceptor agonists, whereas salmeterol was found to be G_s-biased. These findings would facilitate the development of novel drugs for the treatment of both heart failure and asthma.

SUBMITTER: Woo AY

PROVIDER: S-EPMC6786399 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Discovery of β-arrestin-biased β<sub>2</sub>-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.

Woo Anthony Yiu-Ho AY Ge Xin-Yue XY Pan Li L Xing Gang G Mo Yong-Mei YM Xing Rui-Juan RJ Li Xiao-Ran XR Zhang Yu-Yang YY Wainer Irving W IW Cheng Mao-Sheng MS Xiao Rui-Ping RP

Acta pharmacologica Sinica 20190114 8

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 und ...[more]

PMID: 30643208

Similar Datasets

Project description:The β1-adrenoceptor (β1AR) is a G-protein-coupled receptor (GPCR) that couples1 to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of β-arrestin 1 (βarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism3-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the β1AR-βarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound β1AR coupled to the G-protein-mimetic nanobody6 Nb80. βarr1 couples to β1AR in a manner distinct to that7 of Gs coupling to β2AR-the finger loop of βarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal α5 helix of Gs. The conformation of the finger loop in βarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin8. β1AR coupled to βarr1 shows considerable differences in structure compared with β1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of β1AR, and find that formoterol has a lower affinity for the β1AR-βarr1 complex than for the β1AR-Gs complex. The structural differences between these complexes of β1AR provide a foundation for the design of small molecules that could bias signalling in the β-adrenoceptors.

Dataset Information

Discovery of ?-arrestin-biased ?₂-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.

Publications

Discovery of β-arrestin-biased β<sub>2</sub>-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Discovery of ?-arrestin-biased ?2-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.

Publications

Discovery of β-arrestin-biased β<sub>2</sub>-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Discovery of ?-arrestin-biased ?₂-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.