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

The dopamine D receptor (DR) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, DR-selective ligands that can eliminate side effects associated with dopamine D receptor (DR) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between DR and DR have rendered the development of DR-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 DR 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 DR over DR. Functional evaluation revealed that DR-selective ligand displayed a subpicomolar agonist activity at DR 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 DR ligands.