Synthesis and characterization of a bi-directional photoswitchable antagonist toolbox for real-time GPCR photopharmacology,Journal of the American Chemical Society

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Synthesis and characterization of a bi-directional photoswitchable antagonist toolbox for real-time GPCR photopharmacology
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2018-02-22 , DOI: 10.1021/jacs.7b11422
Niels J Hauwert ₁ , Tamara A M Mocking ₁ , Daniel Da Costa Pereira ₁ , Albert J Kooistra ₁ , Lisa M Wijnen ₁ , Gerda C M Vreeker ₁ , Eléonore W E Verweij ₁ , Albertus H De Boer ₁ , Martine J Smit ₁ , Chris De Graaf ₁ , Henry F Vischer ₁ , Iwan J P de Esch ₁ , Maikel Wijtmans ₁ , Rob Leurs ₁

Affiliation

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.

中文翻译：

用于实时 GPCR 光药理学的双向光开关拮抗剂工具箱的合成和表征

非常需要以时间和空间精度调节 G 蛋白偶联受体 (GPCR) 的无创方法。光药理学使用光子来原位控制光可切换小分子配体的生物学特性，这预示着化学生物学精密方法的发展。将偶氮苯的光控构型特性整合到配体核心中，我们为原型 A GPCR 家族（组胺 H3 受体 (H3R)）开发了双向拮抗剂工具箱。从 16 种新合成的光可开关化合物中，选择了 VUF14738 (28) 和 VUF14862 (33)，因为它们在 360 nm 照射下迅速且可逆地发生光异构化，并且 H3R 结合亲和力分别增加或减少了 10 倍以上。两种配体都将长热半衰期与快速和高光化学反式/顺式转换相结合，允许它们用于卵母细胞的实时电生理学实验，以确认在重复的二级循环中 H3R 活化的动态光调制。VUF14738 和 VUF14862 是稳健且抗疲劳的光开关 GPCR 拮抗剂，适用于 H3R 信号传导的时空研究。

更新日期：2018-02-22

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