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

Jiaying Xiong; Jian Jin; Lanchang Gao; Chao Hao; Xin Liu; Bi-Feng Liu; Yin Chen; Guisen Zhang

doi:10.1016/j.ejmech.2020.112144

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. Epub 2020 Feb 14.

Authors

Jiaying Xiong¹, Jian Jin², Lanchang Gao¹, Chao Hao¹, Xin Liu¹, Bi-Feng Liu¹, Yin Chen³, Guisen Zhang⁴

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: 2019000015@jou.edu.cn.
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: gszhang@mail.hust.edu.cn.

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 (K_i σ₁ = 1.86 nM) and μ receptor (K_i 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.

MeSH terms

Amides / administration & dosage
Amides / chemistry
Amides / pharmacology*
Animals
Disease Models, Animal
Dose-Response Relationship, Drug
Formaldehyde
Guinea Pigs
Injections, Subcutaneous
Mice
Mice, Inbred ICR
Molecular Structure
Neuralgia / chemically induced
Neuralgia / drug therapy*
Neuralgia / pathology
Piperidines / administration & dosage
Piperidines / chemistry
Piperidines / pharmacology*
Rats
Rats, Sprague-Dawley
Receptors, Opioid, mu / agonists*
Receptors, sigma / antagonists & inhibitors*
Sciatic Nerve / drug effects
Sciatic Nerve / pathology
Sigma-1 Receptor
Structure-Activity Relationship

Substances

Amides
Piperidines
Receptors, Opioid, mu
Receptors, sigma
Formaldehyde
piperidine
propionamide