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

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ ₁ ) receptor antagonists and mu (μ) opioid receptor agonists, and measured their affinity for σ ₁ 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 σ ₁ receptor (K _i σ ₁  = 1.86 nM) and μ receptor (K _i μ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED ₅₀  = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ ₁ antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ ₁ /μ receptor profiles, may be a potential candidate for treating neuropathic pain.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)