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

[Image: see text] 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 biologic...

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Autores principales: Hauwert, Niels J., Mocking, Tamara A. M., Da Costa Pereira, Daniel, Kooistra, Albert J., Wijnen, Lisa M., Vreeker, Gerda C. M., Verweij, Eléonore W. E., De Boer, Albertus H., Smit, Martine J., De Graaf, Chris, Vischer, Henry F., de Esch, Iwan J. P., Wijtmans, Maikel, Leurs, Rob
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879491/
https://www.ncbi.nlm.nih.gov/pubmed/29470065
http://dx.doi.org/10.1021/jacs.7b11422
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author Hauwert, Niels J.
Mocking, Tamara A. M.
Da Costa Pereira, Daniel
Kooistra, Albert J.
Wijnen, Lisa M.
Vreeker, Gerda C. M.
Verweij, Eléonore W. E.
De Boer, Albertus H.
Smit, Martine J.
De Graaf, Chris
Vischer, Henry F.
de Esch, Iwan J. P.
Wijtmans, Maikel
Leurs, Rob
author_facet Hauwert, Niels J.
Mocking, Tamara A. M.
Da Costa Pereira, Daniel
Kooistra, Albert J.
Wijnen, Lisa M.
Vreeker, Gerda C. M.
Verweij, Eléonore W. E.
De Boer, Albertus H.
Smit, Martine J.
De Graaf, Chris
Vischer, Henry F.
de Esch, Iwan J. P.
Wijtmans, Maikel
Leurs, Rob
author_sort Hauwert, Niels J.
collection PubMed
description [Image: see text] 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 H(3) receptor (H(3)R). 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 H(3)R 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 H(3)R activation in repeated second-scale cycles. VUF14738 and VUF14862 are robust and fatigue-resistant photoswitchable GPCR antagonists suitable for spatiotemporal studies of H(3)R signaling.
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spelling pubmed-58794912018-04-03 Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology Hauwert, Niels J. Mocking, Tamara A. M. Da Costa Pereira, Daniel Kooistra, Albert J. Wijnen, Lisa M. Vreeker, Gerda C. M. Verweij, Eléonore W. E. De Boer, Albertus H. Smit, Martine J. De Graaf, Chris Vischer, Henry F. de Esch, Iwan J. P. Wijtmans, Maikel Leurs, Rob J Am Chem Soc [Image: see text] 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 H(3) receptor (H(3)R). 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 H(3)R 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 H(3)R activation in repeated second-scale cycles. VUF14738 and VUF14862 are robust and fatigue-resistant photoswitchable GPCR antagonists suitable for spatiotemporal studies of H(3)R signaling. American Chemical Society 2018-02-22 2018-03-28 /pmc/articles/PMC5879491/ /pubmed/29470065 http://dx.doi.org/10.1021/jacs.7b11422 Text en Copyright © 2018 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.
spellingShingle Hauwert, Niels J.
Mocking, Tamara A. M.
Da Costa Pereira, Daniel
Kooistra, Albert J.
Wijnen, Lisa M.
Vreeker, Gerda C. M.
Verweij, Eléonore W. E.
De Boer, Albertus H.
Smit, Martine J.
De Graaf, Chris
Vischer, Henry F.
de Esch, Iwan J. P.
Wijtmans, Maikel
Leurs, Rob
Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology
title Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology
title_full Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology
title_fullStr Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology
title_full_unstemmed Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology
title_short Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology
title_sort synthesis and characterization of a bidirectional photoswitchable antagonist toolbox for real-time gpcr photopharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879491/
https://www.ncbi.nlm.nih.gov/pubmed/29470065
http://dx.doi.org/10.1021/jacs.7b11422
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