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An optimized Nurr1 agonist provides disease-modifying effects in Parkinson’s disease models

Authors: Woori Kim, Mohit Tripathi, Chunhyung Kim, Satyapavan Vardhineni, Young Cha, Shamseer Kulangara Kandi, Melissa Feitosa, Rohit Kholiya, Eric Sah, Anuj Thakur, Yehan Kim, Sanghyeok Ko, Kaiya Bhatia, Sunny Manohar, Young-Bin Kong, Gagandeep Sindhu, Yoon-Seong Kim, Bruce Cohen, Diwan S. Rawat, Kwang-Soo Kim


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.

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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)...

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