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

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 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.