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Design, Synthesis, and Evaluation of Bitopic Arylpiperazine-phthalimides as Selective Dopamine D3 Receptor Agonists

Abstract

The dopamine D3 receptor (D3R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D3R-selecitve ligands that can eliminate side effects associated with dopamine D2R receptor (D2R) therapeutics have been validated. However, the high homology in signaling pathways and 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 improved reference compounds 1 and 2 by 9- and 2-times, respectively, and it was 21-fold more potent than compound 2. Molecular docking demonstrated that the orientation of Leu2.64 and Phe7.39 and the packing at the junction of helices may affect the specificity at D3R over D2R. Functional evaluation revealed that D3R-selective ligand 9i displayed subpicomole agonist property at D3R within a 199-fold increase in potency than quinpirole. These results may be useful for the fragment-based design of bitopic compounds as selective D3R ligands.

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Publication details

The article was received on 06 May 2018, accepted on 12 Jun 2018 and first published on 14 Jun 2018


Article type: Research Article
DOI: 10.1039/C8MD00237A
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
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    Design, Synthesis, and Evaluation of Bitopic Arylpiperazine-phthalimides as Selective Dopamine D3 Receptor Agonists

    Y. Cao, N. Sun, J. Zhang, Z. Liu, Y. Tang, Z. wu, K. Kim and S. H. Cheon, Med. Chem. Commun., 2018, Accepted Manuscript , DOI: 10.1039/C8MD00237A

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