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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Niels J. Hauwert
  • Tamara A.M. Mocking
  • Daniel Da Costa Pereira
  • Kooistra, Albert Jelke
  • 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

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

ID: 199351450