2. Academic Validation
  3. GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes

GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes

  • J Med Chem. 2021 Jan 28;64(2):941-957. doi: 10.1021/acs.jmedchem.0c01133.
Congcong Wang 1,  Yu-Fang Zhang 2,  Shimeng Guo 3 4,  Quan Zhao 1,  Yanping Zeng 2,  Zhicheng Xie 2,  Xin Xie 3 4 5 6,  Boxun Lu 1,  Youhong Hu 2 6
Affiliations

Affiliations

  • 1 Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai 200438, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China.
  • 4 CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
PMID: 33185430 DOI: 10.1021/acs.jmedchem.0c01133
Abstract

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.

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