8-Hydroxyquinolin-2(1H)-one analogues as potential β2-agonists: Design, synthesis and activity study

Gang Xing; Zhengxing Zhi; Ce Yi; Jitian Zou; Xuefeng Jing; Anthony Yiu-Ho Woo; Bin Lin; Li Pan; Yuyang Zhang; Maosheng Cheng

doi:10.1016/j.ejmech.2021.113697

8-Hydroxyquinolin-2(1H)-one analogues as potential β₂-agonists: Design, synthesis and activity study

Eur J Med Chem. 2021 Nov 15:224:113697. doi: 10.1016/j.ejmech.2021.113697. Epub 2021 Jul 10.

Authors

Gang Xing¹, Zhengxing Zhi¹, Ce Yi¹, Jitian Zou², Xuefeng Jing³, Anthony Yiu-Ho Woo², Bin Lin¹, Li Pan⁴, Yuyang Zhang⁵, Maosheng Cheng⁶

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
² Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China.
³ General Hospital of Fuxin Mining Industry Group of Liaoning Health Industry Group, Fuxin, 12300, China.
⁴ Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: panli65@aliyun.com.
⁵ Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: 13614053862@163.com.
⁶ Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: mscheng@syphu.edu.cn.

PMID: 34273662
DOI: 10.1016/j.ejmech.2021.113697

Abstract

β₂-Agonists that bind to plasmalemmal β₂-adrenoceptors causing cAMP accumulation are widely used as bronchodilators in chronic respiratory diseases. Here, we designed and synthesized a group of 8-hydroxyquinolin-2(1H)-one analogues and studied their β₂-agonistic activities with a cellular cAMP assay. Compounds B05 and C08 were identified as potent (EC₅₀ < 20 pM) and selective β₂-agonists among the compounds tested. They behaved as partial β₂-agonists in non-overexpressed HEK293 cells, and possessed rapid smooth muscle relaxant actions and long duration of action in isolated guinea pig tracheal strip preparations. In summary, B05 and C08 are β₂-agonists with potential applicability in chronic respiratory diseases.

Keywords: Asthma; COPD; Formoterol; Indacaterol; Olodaterol; β(2)-adrenoceptor agonist.

MeSH terms

Animals
Dose-Response Relationship, Drug
Drug Design*
Guinea Pigs
HEK293 Cells
Humans
Models, Molecular
Molecular Structure
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Receptors, Adrenergic, beta-2 / metabolism*
Structure-Activity Relationship

Substances

8-hydroxyquinolin-2(1H)-one
Quinolines
Receptors, Adrenergic, beta-2