A Photoswitchable Agonist for the Histamine H3 Receptor, a Prototypic Family A G-Protein-Coupled Receptor.
| Title: | A Photoswitchable Agonist for the Histamine H3 Receptor, a Prototypic Family A G-Protein-Coupled Receptor. |
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| Authors: | Hauwert NJ; Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.; Mocking TAM; Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems (AIMMS), 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 (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.; Lion K; Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.; Huppelschoten Y; Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.; Vischer HF; Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems (AIMMS), 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 (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.; Wijtmans M; Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.; Leurs R; Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands. |
| Source: | Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2019 Mar 26; Vol. 58 (14), pp. 4531-4535. Date of Electronic Publication: 2019 Feb 27. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Wiley-VCH Country of Publication: Germany NLM ID: 0370543 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-3773 (Electronic) Linking ISSN: 14337851 NLM ISO Abbreviation: Angew Chem Int Ed Engl Subsets: MEDLINE |
| Imprint Name(s): | Publication: : Weinheim : Wiley-VCH; Original Publication: Weinheim/Bergstr. : New York, : Verlag Chemie ; Academic Press, c1962- |
| MeSH Terms: | Histamine Agonists/*pharmacology ; Receptors, Histamine H3/*metabolism; Histamine Agonists/chemical synthesis ; Histamine Agonists/chemistry ; Humans ; Molecular Structure ; Photochemical Processes |
| Abstract: | Spatiotemporal control over biochemical signaling processes involving G protein-coupled receptors (GPCRs) is highly desired for dissecting their complex intracellular signaling. We developed sixteen photoswitchable ligands for the human histamine H3 receptor (hH3 R). Upon illumination, key compound 65 decreases its affinity for the hH3 R by 8.5-fold and its potency in hH3 R-mediated Gi protein activation by over 20-fold, with the trans and cis isomer both acting as full agonist. In real-time two-electrode voltage clamp experiments in Xenopus oocytes, 65 shows rapid light-induced modulation of hH3 R activity. Ligand 65 shows good binding selectivity amongst the histamine receptor subfamily and has good photolytic stability. In all, 65 (VUF15000) is the first photoswitchable GPCR agonist confirmed to be modulated through its affinity and potency upon photoswitching while maintaining its intrinsic activity, rendering it a new chemical biology tool for spatiotemporal control of GPCR activation.; (© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.) |
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| Grant Information: | 718.014.002 International Nederlandse Organisatie voor Wetenschappelijk Onderzoek |
| Contributed Indexing: | Keywords: H3R; VUF15000; agonism; dynamic modulation; photopharmacology |
| Substance Nomenclature: | 0 (Histamine Agonists); 0 (Receptors, Histamine H3) |
| Entry Date(s): | Date Created: 20190209 Date Completed: 20200908 Latest Revision: 20231012 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC6563694 |
| DOI: | 10.1002/anie.201813110 |
| PMID: | 30735597 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't