In this study, we designed and synthesized twelve bitopic ligands as dopamine D receptor (D R) agonists. The forskolin-induced cAMP accumulation assay revealed that all the finial compounds are able to activate D 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 D R over D R, indicating that the optimal length of spacer affects the D 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 D R functional activity. Taken together, we discovered a bitopic ligand 11 b as potent D R agonist, which may be used as a tool compound for further study.
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