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
  • 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. [email protected].
  • 6. Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA. [email protected].
  • 7. Molecular Neurobiology Laboratory, Program in Neuroscience, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA. [email protected].
  • # 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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