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

被引：48

作者：

Hauwert, Niels J. ^{[1
]}

Mocking, Tamara A. M. ^{[1
]}

Pereira, Daniel Da Costa ^{[1
]}

Kooistra, Albert J. ^{[1
]}

Wijnen, Lisa M. ^{[1
]}

Vreeker, Gerda C. M. ^{[1
]}

Verweij, Eleonore W. E. ^{[1
]}

De Boer, Albertus H. ^{[1
]}

Smit, Martine J. ^{[1
]}

De Graaf, Chris ^{[1
]}

Vischer, Henry F. ^{[1
]}

de Esch, Iwan J. P. ^{[1
]}

Wijtmans, Maikel ^{[1
]}

Leurs, Rob ^{[1
]}

机构：

[1] Vrije Univ Amsterdam, Fac Sci, Amsterdam Inst Mol Med & Syst, Div Med Chem, De Boelelaan 1108, NL-1081 HZ Amsterdam, Netherlands

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2018年 / 140卷 / 12期

关键词：

HISTAMINE H-3 RECEPTOR; OPTICAL CONTROL; SUBSTITUTED AZOBENZENES; TRANS-ISOMERIZATION; H3; RECEPTOR; PROTEIN; LIGANDS; BINDING; POTENT; REFINEMENT;

D O I：

10.1021/jacs.7b11422

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 (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.

引用

页码：4232 / 4243

页数：12

共 63 条

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