Synthesis toward Bivalent Ligands for the Dopamine D₂ and Metabotropic Glutamate 5 Receptors

In this study, we designed and synthesized heterobivalent ligands targeting heteromers consisting of the metabotropic glutamate 5 receptor (mGluR5) and the dopamine D₂ receptor (D₂R). Bivalent ligand 22a with a linker consisting of 20 atoms showed 4-fold increase in affinity for cells coexpressing D₂R and mGluR5 compared to cells solely expressing D₂R. Likewise, the affinity of 22a for mGluR5 increased 2-fold in the coexpressing cells. Additionally, 22a exhibited a 5-fold higher mGluR5 affinity than its monovalent precursor 21a in cells coexpressing D₂R and mGluR5. These results indicate that 22a is able to bridge binding sites on both receptors constituting the heterodimer. Likewise, cAMP assays revealed that 22a had a 4-fold higher potency in stable D₂R and mGluR5 coexpressing cell lines than 1. Furthermore, molecular modeling reveals that 22a is able to simultaneously bind both receptors by passing between the TM5–TM6 interface and establishing six protein–ligand H-bonds.