Photoswitchable Antagonists for a Precise Spatiotemporal Control of β2 -Adrenoceptors

Journal of Medicinal Chemistry
Anna Duran-CorberaXavier Rovira

Abstract

β2-Adrenoceptors (β2-AR) are prototypical G-protein-coupled receptors and important pharmacological targets with relevant roles in physiological processes and diseases. Herein, we introduce Photoazolol-1-3, a series of photoswitchable azobenzene β2-AR antagonists that can be reversibly controlled with light. These new photochromic ligands are designed following the azologization strategy, with a p-acetamido azobenzene substituting the hydrophobic moiety present in many β2-AR antagonists. Using a fluorescence resonance energy transfer (FRET) biosensor-based assay, a variety of photopharmacological properties are identified. Two of the light-regulated molecules show potent β2-AR antagonism and enable a reversible and dynamic control of cellular receptor activity with light. Their photopharmacological properties are opposite, with Photoazolol-1 being more active in the dark and Photoazolol-2 demonstrating higher antagonism upon illumination. In addition, we provide a molecular rationale for the interaction of the different photoisomers with the receptor. Overall, we present innovative tools and a proof of concept for the precise control of β2-AR by means of light.

References

Apr 1, 1984·Physiological Reviews·G L StilesR J Lefkowitz
Feb 1, 1995·Journal of Photochemistry and Photobiology. B, Biology·S Muralidharan, J M Nerbonne
Mar 25, 2011·Trends in Pharmacological Sciences·Jillian G BakerRoger J Summers
Apr 25, 2012·The Journal of Organic Chemistry·Gary A Molander, Livia N Cavalcanti
Feb 13, 2014·Angewandte Chemie·Matthias Schönberger, Dirk Trauner
Sep 24, 2014·Bioconjugate Chemistry·María Isabel BahamondeFrancisco Ciruela
Jun 24, 2015·Accounts of Chemical Research·Johannes BroichhagenDirk Trauner
Sep 29, 2015·Nature Communications·Edward R SiudaMichael R Bruchas
Sep 29, 2015·Accounts of Chemical Research·Mingxin DongG Andrew Woolley
Jul 5, 2016·Angewandte Chemie·Michael M LerchBen L Feringa
Jul 13, 2016·Nature Communications·Michael M LerchBen L Feringa
Oct 6, 2016·Scientific Reports·H C Stephen ChanShuguang Yuan
Dec 3, 2016·Nature Reviews. Drug Discovery·Rita SantosJohn P Overington
Apr 13, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jillian G BakerPeter M Fischer
May 17, 2017·Angewandte Chemie·Luca AgnettaMichael Decker
Jun 27, 2017·Chemistry : a European Journal·Daniel LachmannBurkhard König
Nov 22, 2017·Journal of the American Chemical Society·Matthias V WestphalJames A Frank
Nov 23, 2017·Journal of the American Chemical Society·Prashant C DonthamsettiDirk Trauner
Jun 24, 2018·Trends in Biochemical Sciences·Mark W H Hoorens, Wiktor Szymanski
Jul 10, 2018·Chemical Reviews·Katharina HüllDirk Trauner
Feb 25, 2019·Life Sciences·Khushwant S YadavSushmita Sharma
Mar 14, 2019·Molecular and Cellular Endocrinology·Maria Ricart-OrtegaAmadeu Llebaria
Apr 24, 2019·Journal of the American Chemical Society·Fabio RiefoloPau Gorostiza
May 2, 2019·ACS Central Science·Johannes MorsteinDirk Trauner
Aug 31, 2019·Journal of the American Chemical Society·Natalie L MutterGiovanni Maglia

❮ Previous
Next ❯

Citations

Jun 12, 2021·Journal of the American Chemical Society·Prashant DonthamsettiEhud Y Isacoff

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.