Affiliation:
1. Department of Chemistry and Pharmacy University of Regensburg 93053 Regensburg Germany
2. Department of Chemistry and Pharmacy Friedrich-Alexander University 91058 Erlangen Germany
Abstract
AbstractConverting 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.
Funder
Deutsche Forschungsgemeinschaft
Minerva Foundation
Subject
Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology