Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D3 receptor agonists. Issue 9 (2nd July 2018)

• Record Type: Journal Article
• Authors: Cao, Yongkai; Sun, Ningning; Zhang, Jiumei; Liu, Zhiguo; Tang, Yi-zhe; Wu, Zhengzhi; Kim, Kyeong-Man; Cheon, Seung Hoon
• Is Part Of: MedChemComm. Volume 9:Issue 9(2018)
• Page Start: 1457
• Page End: 1465
• Publication Date: 2018-07-02
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19
• DOI: 10.1039/c8md00237a
• Languages: English
• ISSNs: 2040-2503

Abstract

Abstract : The dopamine D3 receptor (D3 R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. Abstract : The dopamine D3 receptor (D3 R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D3 R-selective ligands that can eliminate side effects associated with dopamine D2 receptor (D2 R) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between D2 R and D3 R have rendered the development of D3 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. Compound9i was identified as the most selective D3 R ligand among these bitopic ligands. Its selectivity was improved compared to reference compounds1 and2 by 9- and 2-fold, respectively, and it was 21-fold more potent than compound2 . 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 D3 R over D2 R. Functional evaluation revealed that D3 R-selective ligand9i displayed a subpicomolar agonist activity at D3 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 D3 R ligands.