Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D 3 receptor agonists

The dopamine D receptor (D R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D R-selective ligands that can eliminate side effects associated with dopamine D receptor (D R) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between D R and D R have rendered the development of D R-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 was identified as the most selective D R ligand among these bitopic ligands. Its selectivity was improved compared to reference compounds and by 9- and 2-fold, respectively, and it was 21-fold more potent than compound . Molecular docking demonstrated that the orientation of Leu and Phe and the packing at the junction of helices may affect the specificity for D R over D R. Functional evaluation revealed that D R-selective ligand displayed a subpicomolar agonist activity at D R 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 D R ligands.