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Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D 3 receptor agonists.
- Source :
-
MedChemComm [Medchemcomm] 2018 Jun 14; Vol. 9 (9), pp. 1457-1465. Date of Electronic Publication: 2018 Jun 14 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- The dopamine D <subscript>3</subscript> receptor (D <subscript>3</subscript> R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D <subscript>3</subscript> R-selective ligands that can eliminate side effects associated with dopamine D <subscript>2</subscript> receptor (D <subscript>2</subscript> R) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between D <subscript>2</subscript> R and D <subscript>3</subscript> R have rendered the development of D <subscript>3</subscript> 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 9i was identified as the most selective D <subscript>3</subscript> R 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 <superscript>2.64</superscript> and Phe <superscript>7.39</superscript> and the packing at the junction of helices may affect the specificity for D <subscript>3</subscript> R over D <subscript>2</subscript> R. Functional evaluation revealed that D <subscript>3</subscript> R-selective ligand 9i displayed a subpicomolar agonist activity at D <subscript>3</subscript> 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 <subscript>3</subscript> R ligands.
Details
- Language :
- English
- ISSN :
- 2040-2511
- Volume :
- 9
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- MedChemComm
- Publication Type :
- Academic Journal
- Accession number :
- 30288220
- Full Text :
- https://doi.org/10.1039/c8md00237a