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) receptor antagonists and mu (μ) opioid receptor agonists, and measured their affinity for σ 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 receptor (K σ = 1.86 nM) and μ receptor (K μ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ/μ receptor profiles, may be a potential candidate for treating neuropathic pain.