Identification of a Novel Subtype-Selective α1B-Adrenoceptor Antagonist

Alaa Abdul-Ridha, Lazarus A. de Zhang, Ashenafi Haileyesus Betrie, Mattia Deluigi, Tasneem M. Vaid, Alice Whitehead, Yifan Zhang, Ben Davis, Richard Harris, Heather Simmonite, Roderick E. Hubbard, Paul R. Gooley, Andreas Plückthun, Ross A.D. Bathgate, David K. Chalmers, Daniel J. Scott*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


α1A-, α1B-, and α1D-adrenoceptors (α1-ARs) are members of the adrenoceptor G protein-coupled receptor family that are activated by adrenaline (epinephrine) and noradrenaline. α1-ARs are clinically targeted using antagonists that have minimal subtype selectivity, such as prazosin and tamsulosin, to treat hypertension and benign prostatic hyperplasia, respectively. Abundant expression of α1-ARs in the heart and central nervous system (CNS) makes these receptors potential targets for the treatment of cardiovascular and CNS disorders, such as heart failure, epilepsy, and Alzheimer’s disease. Our understanding of the precise physiological roles of α1-ARs, however, and their involvement in disease has been hindered by the lack of sufficiently subtype-selective tool compounds, especially for α1B-AR. Here, we report the discovery of 4-[(2-hydroxyethyl)amino]-6-methyl-2H-chromen-2-one (Cpd1), as an α1B-AR antagonist that has 10-15-fold selectivity over α1A-AR and α1D-AR. Through computational and site-directed mutagenesis studies, we have identified the binding site of Cpd1 in α1B-AR and propose the molecular basis of α1B-AR selectivity, where the nonconserved V19745.52 residue plays a major role, with contributions from L3146.55 within the α1B-AR pocket. By exploring the structure-activity relationships of Cpd1 at α1B-AR, we have also identified 3-[(cyclohexylamino)methyl]-6-methylquinolin-2(1H)-one (Cpd24), which has a stronger binding affinity than Cpd1, albeit with reduced selectivity for α1B-AR. Cpd1 and Cpd24 represent potential leads for α1B-AR-selective drug discovery and novel tool molecules to further study the physiology of α1-ARs.

Original languageEnglish
Pages (from-to)671–684
JournalACS Chemical Neuroscience
Issue number3
Early online date18 Jan 2024
Publication statusPublished - 7 Feb 2024

Bibliographical note

Funding Information:
We thank Sharon Layfield and Tania Ferraro (The Florey Institute of Neuroscience and Mental Health) for assistance with cell culture and CRE response assays. We also thank Graham Mackay (Melbourne University, Department of Biochemistry and Pharmacology) for use of the Flexstation. This work was supported by NHMRC project grants 1081801 (D.J.S.) and 1081844 (R.A.D.B., P.R.G., D.J.S); NHMRC ideas grant 2011978; an NHMRC-ARC Dementia Research Development Fellowship (1099692) to A.A.; and an NHMRC Boosting Dementia Research Leadership Fellowship to D.J.S.

Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society

Cite this