2. Academic Validation
  3. Identification and optimization of nitrophenolic analogues as dopamine metabolic enzyme inhibitors for the treatment of Parkinson's disease

Identification and optimization of nitrophenolic analogues as dopamine metabolic enzyme inhibitors for the treatment of Parkinson's disease

  • Bioorg Chem. 2024 Jul:148:107488. doi: 10.1016/j.bioorg.2024.107488.
Manxing Zou 1,  Yulu Wu 2,  Yudan Lan 2,  Huanfang Xie 3,  Haopeng Sun 3,  Wenyuan Liu 4,  Feng Feng 5,  Xueyang Jiang 6
Affiliations

Affiliations

  • 1 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 2 Department of Medicinal Chemistry, Anhui University of Chinese Medicine, Hefei 230012, China.
  • 3 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Department of Pharmaceutical Analysis, Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 211198, China.
  • 5 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; Nanjing Medical University, Nanjing 211198, China.
  • 6 Department of Medicinal Chemistry, Anhui University of Chinese Medicine, Hefei 230012, China. Electronic address: jiang0568@126.com.
PMID: 38797066 DOI: 10.1016/j.bioorg.2024.107488
Abstract

Progressive loss of dopaminergic neurons leads to the depletion of the striatal neurotransmitter dopamine, which is the main cause of Parkinson's disease (PD) motor symptoms. Simultaneous inhibition of the two key dopamine metabolic Enzymes, catechol-O-methyltransferase (COMT) and Monoamine Oxidase B (MAO-B), could potentially be a breakthrough in achieving clinical efficacy. Representative compound C12 exhibits good COMT inhibitory activity (IC50 = 0.37 μM), metal chelation ability, and BBB permeability. Furthermore, results from in vivo biological activity evaluations indicate that C12 can improve dopamine levels and ameliorate MPTP-induced PD symptoms in mice. Preliminary in vivo and in vitro study results highlight the potential of compound C12 in PD treatment.

Keywords

Catechol-O-methyltransferase; Dopamine metabolizing enzymes; Monoamine oxidase; Parkinson’s disease.

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