Design, Synthesis, and Biological Evaluation of Bivalent Ligands Targeting Dopamine D2 -Like Receptors and the μ-Opioid Receptor

Mingcheng Qian, Lakshmi Vasudevan, Jelle Huysentruyt, Martijn D P Risseeuw, Christophe Stove, Patrick M L Vanderheyden, Kathleen Van Craenenbroeck, Serge Van Calenbergh

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Currently, there is mounting evidence that intermolecular receptor-receptor interactions may result in altered receptor recognition, pharmacology and signaling. Heterobivalent ligands have been proven useful as molecular probes for confirming and targeting heteromeric receptors. This report describes the design and synthesis of novel heterobivalent ligands for dopamine D2 -like receptors (D2 -likeR) and the μ-opioid receptor (μOR) and their evaluation using ligand binding and functional assays. Interestingly, we identified a potent bivalent ligand that contains a short 18-atom linker and combines good potency with high efficacy both in β-arrestin 2 recruitment for μOR and MAPK-P for D4 R. Furthermore, this compound was characterized by a biphasic competition binding curve for the D4 R-μOR heterodimer, indicative of a bivalent binding mode. As this compound possibly bridges the D4 R-μOR heterodimer, it could be used as a pharmacological tool to further investigate the interactions of D4 R and μOR.

Original languageEnglish
Pages (from-to)944-956
Number of pages13
JournalChemMedChem
Volume13
Issue number9
DOIs
Publication statusPublished - 8 May 2018

Bibliographical note

© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords

  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Design
  • HEK293 Cells
  • Humans
  • Ligands
  • Molecular Probes/chemical synthesis
  • Molecular Structure
  • Polyethylene Glycols/chemical synthesis
  • Receptors, Dopamine D2/agonists
  • Receptors, Opioid, mu/agonists
  • Structure-Activity Relationship

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