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

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

Open Access

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

Author(s) -

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

Publication year - 2018

Publication title -

journal of the american chemical society

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 7.115

H-Index - 612

eISSN - 1520-5126

pISSN - 0002-7863

DOI - 10.1021/jacs.7b11422

Subject(s) - g protein coupled receptor , chemistry , histamine h3 receptor , azobenzene , antagonist , ligand (biochemistry) , drug discovery , small molecule , receptor , biophysics , combinatorial chemistry , nanotechnology , molecule , biochemistry , biology , organic chemistry , materials science

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 H 3 receptor (H 3 R). 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 H 3 R 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 H 3 R activation in repeated second-scale cycles. VUF14738 and VUF14862 are robust and fatigue-resistant photoswitchable GPCR antagonists suitable for spatiotemporal studies of H 3 R signaling.

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