A Photoswitchable Agonist for the Histamine H 3 Receptor, a Prototypic Family A G-Protein-Coupled Receptor.

Autor: 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.
Jazyk: angličtina
Zdroj: 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.
DOI: 10.1002/anie.201813110
Abstrakt: 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 H 3 receptor (hH 3 R). Upon illumination, key compound 65 decreases its affinity for the hH 3 R by 8.5-fold and its potency in hH 3 R-mediated G i 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 hH 3 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.)
Databáze: MEDLINE
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