1-5-diphenyl-2-penten-1-one and Huntington-Disease

GPR52 is an orphan G protein-coupled receptor (GPCR) highly expressed in the brain, especially in the striatum, and represents an emerging therapeutic target for Huntington's disease (HD), an incurable monogenic neurodegenerative disorder caused by the mutation of the huntingtin (mHTT) gene. This Viewpoint discusses the discovery, published in this journal, that a highly potent and specific GPR52 antagonist was identified through high-throughput screening and structure-activity relationship study, which diminishes not only mHTT protein levels, but also ameliorates HD-like phenotypes in the animal disease models. This strategy offers intriguing promise as a surprising approach for HD therapy, where nucleic acid medicine approaches such as small interference RNAs have been the main focus and encounter obstacles such as delivery efficiency.

Topics: Animals; Drug Discovery; High-Throughput Screening Assays; Humans; Huntingtin Protein; Huntington Disease; Mice; Phenotype; Receptors, G-Protein-Coupled; RNA, Small Interfering; Structure-Activity Relationship

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-

Topics: Animals; Behavior, Animal; Cell Survival; Cells, Cultured; Corpus Striatum; Drug Design; Humans; Huntingtin Protein; Huntington Disease; Mice; Models, Molecular; Neurons; Receptors, G-Protein-Coupled; Structure-Activity Relationship