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 <b>22a</b> 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 <b>22a</b> for mGluR5 increased 2-fold in the coexpressing cells. Additionally, <b>22a</b> exhibited a 5-fold higher mGluR5 affinity than its monovalent precursor <b>21a</b> in cells coexpressing D₂R and mGluR5. These results indicate that <b>22a</b> is able to bridge binding sites on both receptors constituting the heterodimer. Likewise, cAMP assays revealed that <b>22a</b> had a 4-fold higher potency in stable D₂R and mGluR5 coexpressing cell lines than <b>1</b>. Furthermore, molecular modeling reveals that <b>22a</b> is able to simultaneously bind both receptors by passing between the TM5–TM6 interface and establishing six protein–ligand H-bonds.