1 research outputs found
Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology
Noninvasive methods
to modulate G protein-coupled receptors (GPCRs)
with temporal and spatial precision are in great demand. Photopharmacology
uses photons to control <i>in situ</i> 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 H<sub>3</sub> receptor (H<sub>3</sub>R). From 16 newly synthesized photoswitchable compounds, VUF14738
(<b>28</b>) and VUF14862 (<b>33</b>) were selected as
they swiftly and reversibly photoisomerize and show over 10-fold increased
or decreased H<sub>3</sub>R binding affinities, respectively, upon
illumination at 360 nm. Both ligands combine long thermal half-lives
with fast and high photochemical <i>trans</i>-/<i>cis</i> conversion, allowing their use in real-time electrophysiology experiments
with oocytes to confirm dynamic photomodulation of H<sub>3</sub>R
activation in repeated second-scale cycles. VUF14738 and VUF14862
are robust and fatigue-resistant photoswitchable GPCR antagonists
suitable for spatiotemporal studies of H<sub>3</sub>R signaling