Photoswitchable Serotonins for Optical Control of the 5-HT2A Receptor

被引：31

作者：

Morstein, Johannes ^{[1
]}

Romano, Giovanna ^{[2
,3
]}

Hetzler, Belinda E. ^{[1
]}

Plante, Ambrose ^{[2
,3
]}

Haake, Caleb ^{[1
]}

Levitz, Joshua ^{[2
,3
]}

Trauner, Dirk ^{[1
]}

机构：

[1] NYU, Dept Chem, New York, NY 10003 USA

[2] Weill Cornell Med, Physiol Biophys & Syst Biol Grad Program, New York, NY 10065 USA

[3] Weill Cornell Med, Dept Biochem, New York, NY 10065 USA

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2022年 / 61卷 / 18期

基金：

美国国家科学基金会;

关键词：

GPCR; Photopharmacology; Photoswitch; Serotonin; SNAP Tag; AGONIST; DERIVATIVES;

D O I：

10.1002/anie.202117094

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Serotonin receptors play central roles in neuromodulation and are critical drug targets for psychiatric disorders. Optical control of serotonin receptor subtypes has the potential to greatly enhance our understanding of the spatiotemporal dynamics of receptor function. While other neuromodulatory receptors have been successfully rendered photoswitchable, reversible photocontrol of serotonin receptors has not been achieved, representing a major gap in GPCR photopharmacology. Herein, we develop the first tools that allow for such control. Azo5HT-2 shows light-dependent 5-HT2AR agonism, with greater activity in the cis-form. Based on docking and test compound analysis, we also develop photoswitchable orthogonal, remotely-tethered ligands (PORTLs). These BG-Azo5HTs provide rapid, reversible, and repeatable optical control following conjugation to SNAP-tagged 5-HT2AR. Overall, this study provides a foundation for the broad extension of photopharmacology to the serotonin receptor family.

引用

页数：7

共 52 条

[1] Branched Photoswitchable Tethered Ligands Enable Ultra-efficient Optical Control and Detection of G Protein-Coupled Receptors In Vivo [J].