Premium
A Photoswitchable Agonist for the Histamine H 3 Receptor, a Prototypic Family A G‐Protein‐Coupled Receptor
Author(s) -
Hauwert Niels J.,
Mocking Tamara A. M.,
Da Costa Pereira Daniel,
Lion Ken,
Huppelschoten Yara,
Vischer Henry F.,
De Esch Iwan J. P.,
Wijtmans Maikel,
Leurs Rob
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201813110
Subject(s) - agonist , receptor , histamine , histamine receptor , g protein coupled receptor , chemistry , pharmacology , biochemistry , biology , antagonist
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.