Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D₃ receptor agonists

The dopamine D₃ receptor (D₃R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D₃R-selective ligands that can eliminate side effects associated with dopamine D₂ receptor (D₂R) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between D₂R and D₃R have rendered the development of D₃R-selective ligands challenging. Herein, we designed and synthesized a series of piperazine-phthalimide bitopic ligands based on a fragment-based and molecular docking inspired design. Compound 9i was identified as the most selective D₃R ligand among these bitopic ligands. Its selectivity was improved compared to reference compounds 1 and 2 by 9- and 2-fold, respectively, and it was 21-fold more potent than compound 2. Molecular docking demonstrated that the orientation of Leu^2.64 and Phe^7.39 and the packing at the junction of helices may affect the specificity for D₃R over D₂R. Functional evaluation revealed that D₃R-selective ligand 9i displayed a subpicomolar agonist activity at D₃R with a 199-fold increase in potency compared to quinpirole. These results may be useful for the fragment-based design of bitopic compounds as selective D₃R ligands.