Synthesis of bitopic ligands as potent dopamine D2 receptor agonists

In this study, we designed and synthesized twelve bitopic ligands as dopamine D2 receptor (D2R) agonists. The forskolin-induced cAMP accumulation assay revealed that all the finial compounds are able to activate D2R. Furthermore, compound 11b showed 21-fold higher potency than lead compound 2 and 17-fold higher subtype selectivity for D2R over D4R, indicating that the optimal length of spacer affects the D2R functionality. Molecular modeling study exhibited that 11b formed an electrostatic interaction and two H-bonds with amino acid ASP114, which contributes significantly to the D2R functional activity. Taken together, we discovered a bitopic ligand 11b as potent D2R agonist, which may be used as a tool compound for further study.