TY - JOUR
T1 - Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology
AU - Hauwert, Niels J.
AU - Mocking, Tamara A.M.
AU - Da Costa Pereira, Daniel
AU - Kooistra, Albert J.
AU - Wijnen, Lisa M.
AU - Vreeker, Gerda C.M.
AU - Verweij, Eléonore W.E.
AU - De Boer, Albertus H.
AU - Smit, Martine J.
AU - De Graaf, Chris
AU - Vischer, Henry F.
AU - De Esch, Iwan J.P.
AU - Wijtmans, Maikel
AU - Leurs, Rob
PY - 2018/3/28
Y1 - 2018/3/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85044672191&partnerID=8YFLogxK
U2 - 10.1021/jacs.7b11422
DO - 10.1021/jacs.7b11422
M3 - Journal article
C2 - 29470065
AN - SCOPUS:85044672191
SN - 0002-7863
VL - 140
SP - 4232
EP - 4243
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 12
ER -