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. Image 1 • A new series of piperidine propionamide derivatives was designed and synthesized. • Compound 44 showed highest affinities to σ 1 receptor and μ receptor with mixed σ 1 /μ receptor profiles. • Compound 44 performed a dose-dependent analgesic effect in the formalin test. • Compound 44 performed equivalent analgesic effect with S1RA. [ABSTRACT FROM AUTHOR]