GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington’s Disease-Related Phenotypes
| Autor: | Congcong Wang, Quan Zhao, Xin Xie, Yu-Fang Zhang, Boxun Lu, Yanping Zeng, Zhicheng Xie, Youhong Hu, Shimeng Guo |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Huntingtin Cell Survival Pharmacology Receptors G-Protein-Coupled Mice Structure-Activity Relationship Huntington's disease In vivo Drug Discovery medicine Animals Humans Receptor IC50 Cells Cultured G protein-coupled receptor Neurons Huntingtin Protein Gene knockdown Behavior Animal Chemistry Antagonist medicine.disease Corpus Striatum Huntington Disease Drug Design Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 64:941-957 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c01133 |
| Popis: | GPR52 is an orphan G protein-coupled receptor (GPCR) that has been recently implicated as a potential drug target of Huntington's disease (HD), an incurable monogenic neurodegenerative disorder. In this research, we found that striatal knockdown of GPR52 reduces mHTT levels in adult HdhQ140 mice, validating GPR52 as an HD target. In addition, we discovered a highly potent and specific GPR52 antagonist Comp-43 with an IC50 value of 0.63 μM by a structure-activity relationship (SAR) study. Further studies showed that Comp-43 reduces mHTT levels by targeting GPR52 and promotes survival of mouse primary striatal neurons. Moreover, in vivo study showed that Comp-43 not only reduces mHTT levels but also rescues HD-related phenotypes in HdhQ140 mice. Taken together, our study confirms that inhibition of GPR52 is a promising strategy for HD therapy, and the GPR52 antagonist Comp-43 might serve as a lead compound for further investigation. |
| Databáze: | OpenAIRE |
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