Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology
| Autor: | Eléonore W E Verweij, Tamara A. M. Mocking, Daniel Da Costa Pereira, Maikel Wijtmans, Iwan J. P. de Esch, Gerda C M Vreeker, Henry F. Vischer, Albert J. Kooistra, Rob Leurs, Albertus H. de Boer, Martine J. Smit, Chris de Graaf, Niels J Hauwert, Lisa M Wijnen |
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| Přispěvatelé: | AIMMS, Medicinal chemistry, Chemistry and Pharmaceutical Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Ligands
010402 general chemistry 01 natural sciences Biochemistry Article Catalysis Receptors G-Protein-Coupled chemistry.chemical_compound Colloid and Surface Chemistry Biological property Humans Molecule Binding affinities G protein-coupled receptor Photons Molecular Structure 010405 organic chemistry Ligand Antagonist General Chemistry Photochemical Processes 0104 chemical sciences Azobenzene chemistry Biophysics Histamine H3 receptor Azo Compounds |
| Zdroj: | Journal of the American Chemical Society, 140(12), 4232-4243. American Chemical Society Journal of the American Chemical Society Hauwert, N J, Mocking, T A M, Da Costa Pereira, D, Kooistra, A J, Wijnen, L M, Vreeker, G C M, Verweij, E W E, De Boer, A H, Smit, M J, De Graaf, C, Vischer, H F, De Esch, I J P, Wijtmans, M & Leurs, R 2018, ' Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology ', Journal of the American Chemical Society, vol. 140, no. 12, pp. 4232-4243 . https://doi.org/10.1021/jacs.7b11422 |
| ISSN: | 0002-7863 |
| DOI: | 10.1021/jacs.7b11422 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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