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. |
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| Authors: | Hauwert NJ; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Mocking TAM; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Da Costa Pereira D; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Kooistra AJ; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Wijnen LM; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Vreeker GCM; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Verweij EWE; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; De Boer AH; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Smit MJ; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; De Graaf C; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Vischer HF; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; de Esch IJP; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Wijtmans M; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands.; Leurs R; Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science , Vrije Universiteit Amsterdam , De Boelelaan 1108 , 1081 HZ Amsterdam , The Netherlands. |
| Source: | Journal of the American Chemical Society [J Am Chem Soc] 2018 Mar 28; Vol. 140 (12), pp. 4232-4243. Date of Electronic Publication: 2018 Mar 14. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 7503056 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5126 (Electronic) Linking ISSN: 00027863 NLM ISO Abbreviation: J Am Chem Soc Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington, DC : American Chemical Society; Original Publication: Easton, Pa. [etc.] |
| MeSH Terms: | Azo Compounds/*pharmacology ; Receptors, G-Protein-Coupled/*antagonists & inhibitors; Azo Compounds/chemical synthesis ; Azo Compounds/chemistry ; Receptors, G-Protein-Coupled/metabolism ; Humans ; Ligands ; Molecular Structure ; Photochemical Processes ; Photons |
| 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. |
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| Substance Nomenclature: | 0 (Azo Compounds); 0 (Ligands); 0 (Receptors, G-Protein-Coupled); 0 (VUF14738); F0U1H6UG5C (azobenzene) |
| Entry Date(s): | Date Created: 20180223 Date Completed: 20180705 Latest Revision: 20191228 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5879491 |
| DOI: | 10.1021/jacs.7b11422 |
| PMID: | 29470065 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't