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

• Published in: Nature communications 2023-07, Vol.14 (1), p.4283-4283, Article 4283
• Main 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
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/51; 14/1; 14/33; 14/63; 38/35; 38/47; 38/70; 38/88; 42/44; 631/378/1689/1718; 631/378/1934; 64/60; 692/308/153; 82/16; 82/58; 82/83; Abnormalities; Agonists; Amodiaquine; Animal models; Animals; Brain - metabolism; Chloroquine; Disease Models, Animal; Dopamine; Dopaminergic Neurons - metabolism; Dyskinesia; Humanities and Social Sciences; Male; Males; Mesencephalon; Mesencephalon - metabolism; Mice; Movement disorders; MPTP; multidisciplinary; Neurodegenerative diseases; Neurons; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism; Nuclear receptors; Nurr1 protein; Parkinson Disease - drug therapy; Parkinson Disease - pathology; Parkinson's disease; Risk factors; Science; Science (multidisciplinary); Synuclein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39970-9

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.