Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology

Journal of the American Chemical Society
Niels J HauwertRob Leurs

Abstract

Noninvasive methods to modulate G protein-coupled receptors (GPCRs) with temporal and spatial precision are in great demand. Photopharmacology uses photons to control in situ the biological properties of photoswitchable small-molecule ligands, which bodes well for chemical biological precision approaches. Integrating the light-switchable configurational properties of an azobenzene into the ligand core, we developed a bidirectional antagonist toolbox for an archetypical family A GPCR, the histamine H3 receptor (H3R). From 16 newly synthesized photoswitchable compounds, VUF14738 (28) and VUF14862 (33) were selected as they swiftly and reversibly photoisomerize and show over 10-fold increased or decreased H3R binding affinities, respectively, upon illumination at 360 nm. Both ligands combine long thermal half-lives with fast and high photochemical trans-/ cis conversion, allowing their use in real-time electrophysiology experiments with oocytes to confirm dynamic photomodulation of H3R activation in repeated second-scale cycles. VUF14738 and VUF14862 are robust and fatigue-resistant photoswitchable GPCR antagonists suitable for spatiotemporal studies of H3R signaling.

References

May 14, 1987·Nature·J M ArrangJ C Schwartz
Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Aug 1, 1996·British Journal of Pharmacology·A Alves-RodriguesH Timmerman
Apr 19, 2002·The Journal of Pharmacology and Experimental Therapeutics·Albert J UvegesPhilip G Jones
Feb 4, 2003·Nature Reviews. Neuroscience·Helmut Haas, Pertti Panula
Jan 25, 2005·Nature Reviews. Drug Discovery·Rob LeursIwan J P de Esch
Mar 18, 2005·Journal of Medicinal Chemistry·Curt A DvorakNicholas I Carruthers
Aug 9, 2005·Bioorganic & Medicinal Chemistry·Simone LorenziPier Vincenzo Plazzi
Dec 27, 2005·Drug Discovery Today·Sylvain CelanireIwan J P de Esch
Jan 3, 2006·Journal of Molecular Graphics & Modelling·Frank U AxeSándor Szalma
Sep 29, 2006·Journal of Medicinal Chemistry·Julian Tirado-Rives, William L Jorgensen
Jan 24, 2007·Journal of Chemical Information and Modeling·Gilles Marcou, Didier Rognan
Feb 16, 2007·Angewandte Chemie·Lars V SchäferHelmut Grubmüller
Jun 1, 2007·European Journal of Pharmacology·Kristoffer SahlholmPeter Arhem
Jul 9, 2008·Bioorganic & Medicinal Chemistry Letters·Olivier RocheRosa Maria Rodriguez Sarmiento
Jan 8, 2009·Journal of Chemical Information and Modeling·Oliver KorbThomas E Exner
Feb 9, 2010·Bioorganic & Medicinal Chemistry Letters·Kerstin SanderHolger Stark
Mar 3, 2010·Annual Review of Biophysics·Stephanie Szobota, Ehud Y Isacoff
Jan 26, 2011·Current Topics in Medicinal Chemistry·Evan P LeboisCraig W Lindsley
Mar 19, 2011·Trends in Pharmacological Sciences·Rob LeursIwan J P de Esch
Apr 13, 2011·Chemical Society Reviews·Andrew A Beharry, G Andrew Woolley
May 28, 2011·British Journal of Pharmacology·Jean-Charles Schwartz
Oct 11, 2011·Journal of the American Chemical Society·Peter SchmidtkeXavier Barril
Nov 1, 2011·Journal of Chemical Information and Modeling·Soo-Kyung KimWilliam A Goddard
Sep 13, 2012·Angewandte Chemie·Marco SteinDirk Trauner
Sep 29, 2012·Beilstein Journal of Organic Chemistry·Jaume García-Amorós, Dolores Velasco
Mar 23, 2013·Science·Daniel WackerRaymond C Stevens
Apr 26, 2013·Chemical Reviews·Wiktor SzymańskiBen L Feringa
May 30, 2013·British Journal of Pharmacology·A J KooistraC de Graaf
Jun 22, 2013·Bioorganic & Medicinal Chemistry·Nicolas LevoinMarc Capet
Jan 25, 2014·Journal of the American Chemical Society·Willem A VelemaBen L Feringa
Feb 13, 2014·Angewandte Chemie·Matthias Schönberger, Dirk Trauner
Aug 12, 2014·Nature Chemical Biology·J Robert LaneArthur Christopoulos
Sep 1, 2014·Nature Chemical Biology·Silvia PittoloPau Gorostiza
Sep 24, 2014·Bioconjugate Chemistry·María Isabel BahamondeFrancisco Ciruela
Oct 15, 2014·Nature Communications·Johannes BroichhagenDirk Trauner
May 23, 2015·Nature Communications·James Allen FrankDirk Trauner
Jun 19, 2015·Pharmacological Reviews·Pertti PanulaHelmut L Haas
Jun 23, 2015·Angewandte Chemie·David Bléger, Stefan Hecht
Jun 24, 2015·Accounts of Chemical Research·Johannes BroichhagenDirk Trauner
Jul 16, 2015·Chemical Communications : Chem Comm·M DongG A Woolley
Mar 13, 2012·Journal of Chemical Theory and Computation·Arnau CordomíLeonardo Pardo

❮ Previous
Next ❯

Citations

Jun 12, 2019·Expert Opinion on Drug Discovery·Alexey MishinVadim Cherezov
Nov 5, 2019·Physical Chemistry Chemical Physics : PCCP·Bernard MravecMarek Cigáň
Nov 16, 2019·Beilstein Journal of Organic Chemistry·Xavier Gómez-SantacanaRob Leurs
Apr 18, 2019·Beilstein Journal of Organic Chemistry·Karin RustlerBurkhard König
Dec 15, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gábor WágnerRob Leurs
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Pakhuri MehtaSławomir Filipek
Jun 12, 2021·Journal of the American Chemical Society·Prashant DonthamsettiEhud Y Isacoff
Jul 30, 2021·The Journal of Organic Chemistry·Bernard MravecMarek Cigáň
Apr 25, 2020·Journal of the American Chemical Society·Xingye YangMinyong Li
Jul 10, 2018·Chemical Reviews·Katharina HüllDirk Trauner
Jul 21, 2020·Journal of Medicinal Chemistry·Anna Duran-CorberaXavier Rovira
Jan 6, 2021·Journal of the American Chemical Society·Roman C SarottJames A Frank
Dec 17, 2021·Journal of Agricultural and Food Chemistry·Yaoyao DuXusheng Shao

❮ Previous
Next ❯

Methods Mentioned

BETA
NMR
column
transfection
competition binding
Assay

Software Mentioned

pClamp
MOE
Graphpad prism
IFP
PLANTS
MODELER
Mathworks Matlab
Graphpad
GAFF

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.

Related Papers

The International Journal of Biochemistry & Cell Biology
Arun K Shukla
Progress in Medicinal Chemistry
H StarkW Schunack
© 2022 Meta ULC. All rights reserved