Development of Photoswitchable Tethered Ligands that Target the μ-Opioid Receptor

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL ChemMedChem Pub Date : 2023-10-10 DOI:10.1002/cmdc.202300228

Ranit Lahmy, Dr. Harald Hübner, Dr. Daniel Lachmann, Prof. Dr. Peter Gmeiner, Prof. Dr. Burkhard König

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Abstract

Converting known ligands into photoswitchable derivatives offers the opportunity to modulate compound structure with light and hence, biological activity. In doing so, these probes provide unique control when evaluating G-protein-coupled receptor (GPCR) mechanism and function. Further conversion of such compounds into covalent probes, known as photoswitchable tethered ligands (PTLs), offers additional advantages. These include localization of the PTLs to the receptor binding pocket. Covalent localization increases local ligand concentration, improves site selectivity and may improve the biological differences between the respective isomers. This work describes chemical, photophysical and biochemical characterizations of a variety of PTLs designed to target the μ-opioid receptor (μOR). These PTLs were modeled on fentanyl, with the lead disulfide-containing agonist found to covalently interact with a cysteine-enriched mutant of this medically-relevant receptor.

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靶向µ-阿片受体的可光开关系链配体的开发。

将已知配体转化为光开关衍生物提供了用光调节化合物结构的机会，从而调节生物活性。这样，这些探针在评估G蛋白偶联受体（GPCR）机制和功能时提供了独特的控制。将这些化合物进一步转化为共价探针，即光开关束缚配体（PTL），提供了额外的优势。这些包括将PTL定位到受体结合口袋。共价定位增加了局部配体浓度，提高了位点选择性，并可能改善各自异构体之间的生物差异。这项工作描述了各种旨在靶向µ-阿片受体（µOR）的PTL的化学、光物理和生物化学特征。这些PTL以芬太尼为模型，发现含有二硫化铅的激动剂与这种医学相关受体共价相互作用。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.