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Design, Synthesis, and Biological Evaluation of Bivalent Ligands Targeting Dopamine D 2 ‐Like Receptors and the μ‐Opioid Receptor
Author(s) -
Qian Mingcheng,
Vasudevan Lakshmi,
Huysentruyt Jelle,
Risseeuw Martijn D. P.,
Stove Christophe,
Vanderheyden Patrick M. L.,
Van Craenenbroeck Kathleen,
Van Calenbergh Serge
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700787
Subject(s) - bivalent (engine) , receptor , chemistry , linker , g protein coupled receptor , dopamine receptor d2 , opioid receptor , stereochemistry , cricetulus , opioid , pharmacology , biophysics , biochemistry , biology , organic chemistry , computer science , metal , operating system , chinese hamster ovary cell
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 D 2 ‐like receptors (D 2 ‐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 D 4 R. Furthermore, this compound was characterized by a biphasic competition binding curve for the D 4 R–μOR heterodimer, indicative of a bivalent binding mode. As this compound possibly bridges the D 4 R–μOR heterodimer, it could be used as a pharmacological tool to further investigate the interactions of D 4 R and μOR.