Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology

Niels J. Hauwert, Tamara A.M. Mocking, Daniel Da Costa Pereira, Albert J. Kooistra, Lisa M. Wijnen, Gerda C.M. Vreeker, Eléonore W.E. Verweij, Albertus H. De Boer, Martine J. Smit, Chris De Graaf, Henry F. Vischer, Iwan J.P. De Esch, Maikel Wijtmans*, Rob Leurs

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Noninvasive methods to modulate G protein-coupled receptors (GPCRs) with temporal and spatial precision are in great demand. Photopharmacology uses photons to control in situ the biological properties of photoswitchable small-molecule ligands, which bodes well for chemical biological precision approaches. Integrating the light-switchable configurational properties of an azobenzene into the ligand core, we developed a bidirectional antagonist toolbox for an archetypical family A GPCR, the histamine H3 receptor (H3R). From 16 newly synthesized photoswitchable compounds, VUF14738 (28) and VUF14862 (33) were selected as they swiftly and reversibly photoisomerize and show over 10-fold increased or decreased H3R binding affinities, respectively, upon illumination at 360 nm. Both ligands combine long thermal half-lives with fast and high photochemical trans-/cis conversion, allowing their use in real-time electrophysiology experiments with oocytes to confirm dynamic photomodulation of H3R activation in repeated second-scale cycles. VUF14738 and VUF14862 are robust and fatigue-resistant photoswitchable GPCR antagonists suitable for spatiotemporal studies of H3R signaling.

Original languageEnglish
Pages (from-to)4232-4243
Number of pages12
JournalJournal of the American Chemical Society
Issue number12
Publication statusPublished - 28 Mar 2018


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