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

Index: 10.1002/cmdc.201700787

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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 D4R. Furthermore, this compound was characterized by a biphasic competition binding curve for the D4R–μOR heterodimer, indicative of a bivalent binding mode. As this compound possibly bridges the D4R–μOR heterodimer, it could be used as a pharmacological tool to further investigate the interactions of D4R and μOR.