한빛사논문
- 조회874
Woori Kim 1,2,5, Mohit Tripathi 3,5, Chunhyung Kim 1,2, Satyapavan Vardhineni 3, Young Cha 1,2, Shamseer Kulangara Kandi 3, Melissa Feitosa 1,2, Rohit Kholiya3,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 3,* & Kwang-Soo Kim 1,2,*
1Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
2Molecular Neurobiology Laboratory, Program in Neuroscience, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
3Department of Chemistry, University of Delhi, Delhi 110007, India.
4Institute for Neurological Therapeutics, Rutgers University, Piscataway, NJ 08854, USA.
5These authors contributed equally: Woori Kim, Mohit Tripathi.
*Corresponding author: correspondence to Diwan S. Rawat or 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.
논문정보
- Research article
- 2023년 07월 (BRIC 등록일 2023-07-21)
- 국외 연구진
- 생명과학 > 신경생물학
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