A Photoswitchable Dualsteric Ligand Controlling Receptor Efficacy

被引：56

作者：

Agnetta, Luca ^{[1
]}

Kauk, Michael ^{[2
,3
]}

Canizal, Maria Consuelo Alonso ^{[2
,3
]}

Messerer, Regina ^{[1
]}

Holzgrabe, Ulrike ^{[1
]}

Hoffmann, Carsten ^{[2
,3
,4
]}

Decker, Michael ^{[1
]}

机构：

[1] Julius Maximilian Univ Wurzburg, Pharmaceut & Med Chem, Inst Pharm & Food Chem, D-97074 Wurzburg, Germany

[2] Julius Maximilian Univ Wurzburg, Dept Pharmacol & Toxicol, Versbacher Str 9, D-97078 Wurzburg, Germany

[3] Julius Maximilian Univ Wurzburg, Rudolf Virchow Ctr Expt Biomed, Josef Schneider Str 2, D-97080 Wurzburg, Germany

[4] Friedrich Schiller Univ Jena, Univ Hosp Jena, Ctr Mol Biomed, Inst Mol Cell Biol, Hans Knoll Str 2, D-07745 Jena, Germany

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2017年 / 56卷 / 25期

关键词：

acetylcholine receptors; azobenzenes; dualsteric ligands; G-protein-coupled receptors; photopharmacology; MUSCARINIC ACETYLCHOLINE-RECEPTOR; PROTEIN-COUPLED RECEPTORS; BITOPIC LIGANDS; LIVING CELLS; ALZHEIMERS-DISEASE; ACTIVATION; PHOTOPHARMACOLOGY; AGONISTS; FRET;

D O I：

10.1002/anie.201701524

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The investigation of the mode and time course of the activation of G-protein-coupled receptors (GPCRs), in particular muscarinic acetylcholine (mACh or M) receptors, is still in its infancy despite the tremendous therapeutic relevance of M receptors and GPCRs in general. We herein made use of a dualsteric ligand that can concomitantly interact with the orthosteric, that is, the neurotransmitter, binding site and an allosteric one. We synthetically incorporated a photoswitchable (photochromic) azobenzene moiety. We characterized the photophysical properties of this ligand called BQCAAI and investigated its applicability as a pharmacological tool compound with a set of FRET techniques at the M-1 receptor. BQCAAI proved to be an unprecedented molecular tool; it is the first photoswitchable dualsteric ligand, and its activity can be regulated by light. We also applied BQCCAI to investigate the time course of several receptor activation processes.

引用

页码：7282 / 7287

页数：6

共 34 条

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