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

J Med Chem. 2018 Sep 27;61(18):8212-8225. doi: 10.1021/acs.jmedchem.8b00671. Epub 2018 Sep 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclic AMP / metabolism
  • Dopamine / metabolism*
  • Drug Design*
  • Glutamates / metabolism*
  • HEK293 Cells
  • Humans
  • Ligands
  • Radioligand Assay
  • Receptor, Metabotropic Glutamate 5 / chemistry*
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Receptors, Dopamine D2 / chemistry*
  • Receptors, Dopamine D2 / metabolism*
  • Small Molecule Libraries
  • Structure-Activity Relationship


  • GRM5 protein, human
  • Glutamates
  • Ligands
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Dopamine D2
  • Small Molecule Libraries
  • Cyclic AMP
  • Dopamine