Piperidine propionamide as a scaffold for potent sigma-1 receptor antagonists and mu opioid receptor agonists for treating neuropathic pain

  • Eur J Med Chem. 2020 Apr 1;191:112144. doi: 10.1016/j.ejmech.2020.112144.
Jiaying Xiong  1 ,  Jian Jin  2 ,  Lanchang Gao  1 ,  Chao Hao  1 ,  Xin Liu  1 ,  Bi-Feng Liu  1 ,  Yin Chen  3 ,  Guisen Zhang  4
Affiliations
  • 1. Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
  • 2. Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China.
  • 3. Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China. Electronic address: [email protected].
  • 4. Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China; Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China. Electronic address: [email protected].
PMID: 32087465 DOI: 10.1016/j.ejmech.2020.112144
Abstract

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ1) receptor antagonists and mu (μ) Opioid Receptor agonists, and measured their affinity for σ1 and μ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ1 receptor (Ki σ1 = 1.86 nM) and μ receptor (Ki μ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED50 = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ1 antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ1/μ receptor profiles, may be a potential candidate for treating neuropathic pain.

Keywords
Analgesic; Mu receptor agonists; Piperidine propionamide; Sigma-1 receptor antagonists.
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