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- Title
An optimized Nurr1 agonist provides disease-modifying effects in Parkinson's disease models.
- Authors
Kim, Woori; Tripathi, Mohit; Kim, Chunhyung; Vardhineni, Satyapavan; Cha, Young; Kandi, Shamseer Kulangara; Feitosa, Melissa; Kholiya, Rohit; Sah, Eric; Thakur, Anuj; Kim, Yehan; Ko, Sanghyeok; Bhatia, Kaiya; Manohar, Sunny; Kong, Young-Bin; Sindhu, Gagandeep; Kim, Yoon-Seong; Cohen, Bruce; Rawat, Diwan S.; Kim, Kwang-Soo
- Abstract
The nuclear receptor, Nurr1, is critical for both the development and maintenance of midbrain dopamine neurons, representing a promising molecular target for Parkinson's disease (PD). We previously identified three Nurr1 agonists (amodiaquine, chloroquine and glafenine) that share an identical chemical scaffold, 4-amino-7-chloroquinoline (4A7C), suggesting a structure-activity relationship. Herein we report a systematic medicinal chemistry search in which over 570 4A7C-derivatives were generated and characterized. Multiple compounds enhance Nurr1's transcriptional activity, leading to identification of an optimized, brain-penetrant agonist, 4A7C-301, that exhibits robust neuroprotective effects in vitro. In addition, 4A7C-301 protects midbrain dopamine neurons in the MPTP-induced male mouse model of PD and improves both motor and non-motor olfactory deficits without dyskinesia-like behaviors. Furthermore, 4A7C-301 significantly ameliorates neuropathological abnormalities and improves motor and olfactory dysfunctions in AAV2-mediated α-synuclein-overexpressing male mouse models. These disease-modifying properties of 4A7C-301 may warrant clinical evaluation of this or analogous compounds for the treatment of patients with PD. An optimized agonist of Nurr1, 4A7C-301, protects dopamine neurons against environmental and genetic risk factors of Parkinson's disease (PD) in vitro, and improves both motor and non-motor deficits in male rodent models of PD.
- Subjects
PARKINSON'S disease; DOPAMINERGIC neurons; MALE models; DRUG target; PHARMACEUTICAL chemistry; SMELL disorders
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-39970-9