2. Academic Validation
  3. Design, Synthesis, and Characterization of New δ Opioid Receptor-Selective Fluorescent Probes and Applications in Single-Molecule Microscopy of Wild-Type Receptors

Design, Synthesis, and Characterization of New δ Opioid Receptor-Selective Fluorescent Probes and Applications in Single-Molecule Microscopy of Wild-Type Receptors

  • J Med Chem. 2024 Aug 8;67(15):12618-12631. doi: 10.1021/acs.jmedchem.4c00627.
Antonios Drakopoulos 1,  Zsombor Koszegi 2 3,  Kerstin Seier 4,  Harald Hübner 5,  Damien Maurel 6,  Rémy Sounier 6,  Sébastien Granier 6,  Peter Gmeiner 5,  Davide Calebiro 2 3,  Michael Decker 1
Affiliations

Affiliations

  • 1 Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität (JMU) Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • 2 Institute of Metabolism and Systems Research, University of Birmingham, B15 2TT Birmingham, U.K.
  • 3 Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, B15 2TT Birmingham, U.K.
  • 4 Institute of Pharmacology and Toxicology, Julius-Maximilians University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
  • 5 Chair of Pharmaceutical Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nürnberg, 91058 Erlangen, Germany.
  • 6 Institut de Génomique Fonctionnelle, CNRS, INSERM, Université de Montpellier, 34094 Cedex 5 Montpellier, France.
PMID: 39044606 DOI: 10.1021/acs.jmedchem.4c00627
Abstract

The delta Opioid Receptor (δOR or DOR) is a G protein-coupled receptor (GPCR) showing a promising profile as a drug target for nociception and analgesia. Herein, we design and synthesize new fluorescent antagonist probes with high δOR selectivity that are ideally suited for single-molecule microscopy (SMM) applications in unmodified, untagged receptors. Using our new probes, we investigated wild-type δOR localization and mobility at low physiological receptor densities for the first time. Furthermore, we investigate the potential formation of δOR homodimers, as such a receptor organization might exhibit distinct pharmacological activity, potentially paving the way for innovative pharmacological therapies. Our findings indicate that the majority of δORs labeled with these probes exist as freely diffusing monomers on the cell surface in a simple cell model. This discovery advances our understanding of OR behavior and offers potential implications for future therapeutic research.

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