2. Academic Validation
  3. An optimized Nurr1 agonist provides disease-modifying effects in Parkinson's disease models

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

  • Nat Commun. 2023 Jul 18;14(1):4283. doi: 10.1038/s41467-023-39970-9.
Woori Kim # 1 2,  Mohit Tripathi # 3,  Chunhyung Kim 1 2,  Satyapavan Vardhineni 3,  Young Cha 1 2,  Shamseer Kulangara Kandi 3,  Melissa Feitosa 1 2,  Rohit Kholiya 3,  Eric Sah 1 2,  Anuj Thakur 3,  Yehan Kim 1 2,  Sanghyeok Ko 1 2,  Kaiya Bhatia 1 2,  Sunny Manohar 3,  Young-Bin Kong 1 2,  Gagandeep Sindhu 3,  Yoon-Seong Kim 4,  Bruce Cohen 1,  Diwan S Rawat 5,  Kwang-Soo Kim 6 7
Affiliations

Affiliations

  • 1 Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA.
  • 2 Molecular Neurobiology Laboratory, Program in Neuroscience, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA.
  • 3 Department of Chemistry, University of Delhi, Delhi, 110007, India.
  • 4 Institute for Neurological Therapeutics, Rutgers University, Piscataway, NJ, 08854, USA.
  • 5 Department of Chemistry, University of Delhi, Delhi, 110007, India. dsrawat@chemistry.du.ac.in.
  • 6 Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA. kskim@mclean.harvard.edu.
  • 7 Molecular Neurobiology Laboratory, Program in Neuroscience, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA. kskim@mclean.harvard.edu.
  • # Contributed equally.
PMID: 37463889 DOI: 10.1038/s41467-023-39970-9
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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