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Selective and Wash‐Resistant Fluorescent Dihydrocodeinone Derivatives Allow Single‐Molecule Imaging of μ‐Opioid Receptor Dimerization
Author(s) -
Gentzsch Christian,
Seier Kerstin,
Drakopoulos Antonios,
Jobin MarieLise,
Lanoiselée Yann,
Koszegi Zsombor,
Maurel Damien,
Sounier Rémy,
Hübner Harald,
Gmeiner Peter,
Granier Sébastien,
Calebiro Davide,
Decker Michael
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201912683
Subject(s) - chemistry , fluorescence , receptor , opioid receptor , biophysics , opioid , antagonist , molecule , small molecule , membrane , stereochemistry , biochemistry , biology , physics , organic chemistry , quantum mechanics
Abstract μ‐Opioid receptors (μ‐ORs) play a critical role in the modulation of pain and mediate the effects of the most powerful analgesic drugs. Despite extensive efforts, it remains insufficiently understood how μ‐ORs produce specific effects in living cells. We developed new fluorescent ligands based on the μ‐OR antagonist E‐p ‐nitrocinnamoylamino‐dihydrocodeinone (CACO), that display high affinity, long residence time and pronounced selectivity. Using these ligands, we achieved single‐molecule imaging of μ‐ORs on the surface of living cells at physiological expression levels. Our results reveal a high heterogeneity in the diffusion of μ‐ORs, with a relevant immobile fraction. Using a pair of fluorescent ligands of different color, we provide evidence that μ‐ORs interact with each other to form short‐lived homodimers on the plasma membrane. This approach provides a new strategy to investigate μ‐OR pharmacology at single‐molecule level.