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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Wang C,Zhang YF,Guo S,Zhao Q,Zeng Y,Xie Z,Xie X,Lu B,Hu Ydoi
10.1021/acs.jmedchem.0c01133subject
Has Abstractpub_date
2021-01-28 00:00:00pages
941-957issue
2eissn
0022-2623issn
1520-4804journal_volume
64pub_type
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