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 (sigma(1)) receptor antagonists and mu (mu) opioid receptor agonists, and measured their affinity for sigma(1) and mu 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 sigma(1) receptor (K-i sigma(1) = 1.86 nM) and mu receptor (K-i mu = 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 (sigma(1) antagonist) in a CCI model. Therefore, Compound 44, which has mixed sigma(1)/mu receptor profiles, may be a potential candidate for treating neuropathic pain. (c) 2020 Elsevier Masson SAS. All rights reserved.