Synthesis of Bitopic Ligands as Potent Dopamine D2 Receptor Agonists.

In this study, we designed and synthesized twelve bitopic ligands as dopamine D2 receptor (D2 R) agonists. The forskolin-induced cAMP accumulation assay revealed that all the finial compounds are able to activate D2 R. Furthermore, bitopic ligand N-((trans)-4-(((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclo-hexyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (11 b) showed 21-fold higher potency than lead compound propyl aminoindane (2) and 17-fold higher subtype selectivity for D2 R over D4 R, indicating that the optimal length of spacer affects the D2 R functionality. Molecular modeling study exhibited that 11 b formed an electrostatic interaction and two H-bonds with amino acid Asp114, which contributes significantly to the D2 R functional activity. Taken together, we discovered a bitopic ligand 11 b as potent D2 R agonist, which may be used as a tool compound for further study.