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

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 receptor (hH R). Upon illumination, key compound 65...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie International Edition 2019-03, Vol.58 (14), p.4531-4535
Main Authors: 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
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 receptor (hH R). Upon illumination, key compound 65 decreases its affinity for the hH R by 8.5-fold and its potency in hH R-mediated G 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 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.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201813110