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

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.