Selective and Wash-Resistant Fluorescent Dihydrocodeinone Derivatives Allow Single-Molecule Imaging of μ-Opioid Receptor Dimerization.

Autor: Gentzsch C; Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius Maximilian University of Würzburg, Am Hubland, 97074, Würzburg, Germany., Seier K; Institute of Pharmacology and Toxicology, Julius Maximilian University of Würzburg, Versbacher Strasse 9, 97078, Würzburg, Germany., Drakopoulos A; Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius Maximilian University of Würzburg, Am Hubland, 97074, Würzburg, Germany., Jobin ML; Institute of Pharmacology and Toxicology, Julius Maximilian University of Würzburg, Versbacher Strasse 9, 97078, Würzburg, Germany., Lanoiselée Y; Institute of Metabolism and Systems Research & Centre of Membrane Proteins and Receptors, University of Birmingham, IBR Tower, Level 2, Edgbaston, Birmingham, B152TT, UK., Koszegi Z; Institute of Metabolism and Systems Research & Centre of Membrane Proteins and Receptors, University of Birmingham, IBR Tower, Level 2, Edgbaston, Birmingham, B152TT, UK., Maurel D; ARPEGE (Pharmacology Screening Interactome) platform facility, Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 141, rue de la Cardonille, 34094, Montpellier Cedex 05, France., Sounier R; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 141, rue de la Cardonille, 34094, Montpellier Cedex 05, France., Hübner H; Medicinal Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg, 91058, Erlangen, Germany., Gmeiner P; Medicinal Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg, 91058, Erlangen, Germany., Granier S; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 141, rue de la Cardonille, 34094, Montpellier Cedex 05, France., Calebiro D; Institute of Pharmacology and Toxicology, Julius Maximilian University of Würzburg, Versbacher Strasse 9, 97078, Würzburg, Germany.; Institute of Metabolism and Systems Research & Centre of Membrane Proteins and Receptors, University of Birmingham, IBR Tower, Level 2, Edgbaston, Birmingham, B152TT, UK., Decker M; Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius Maximilian University of Würzburg, Am Hubland, 97074, Würzburg, Germany.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2020 Apr 06; Vol. 59 (15), pp. 5958-5964. Date of Electronic Publication: 2020 Jan 07.
DOI: 10.1002/anie.201912683
Abstrakt: 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.
(© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)
Databáze: MEDLINE
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