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

Niels J. Hauwert, Tamara A.M. Mocking, Daniel Da Costa Pereira, Ken Lion, Yara Huppelschoten, Henry F. Vischer, Iwan J.P. De Esch, Maikel Wijtmans*, Rob Leurs

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)4531-4535
Number of pages5
JournalAngewandte Chemie. International Edition
Issue number14
Early online date8 Feb 2019
Publication statusPublished - 26 Mar 2019


We acknowledge The Netherlands Organisation for Scientific Research (NWO) for financial support (TOPPUNT, “7 ways to 7TMR modulation (7-to-7)”, 718.014.002). All authors participate in the European Cooperation in Science and Technology Action CM1207 [GPCR-Ligand Interactions, Structures, and Transmembrane Signaling: A European Research Network (GLISTEN)]. We thank Hans Custers for HRMS analyses, Andrea van de Stolpe for setting up the photochemistry equipment and Fons Lefeber (Leiden University) for NMR assistance. Kristoffer Sahlholm (Karolinska institute) is kindly acknowledged for providing the pcDNA3.1-Kir3.1 and -Kir3.4 plasmids.

FundersFunder number
European Cooperation in Science and TechnologyCM1207
Universiteit Leiden
Nederlandse Organisatie voor Wetenschappelijk Onderzoek7-to-7, 718.014.002
Karolinska Institutet


    • agonism
    • dynamic modulation
    • H R
    • photopharmacology
    • VUF15000


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