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To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional μ opioid receptor (MOR) and σ 1 receptor (σ 1 R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (K i  = 6.5 nΜ; EC 50  = 48.5 nΜ, E max  = 66.3%) and σ 1 R antagonism (K i  = 35.7 nM) in vitro, and exerted powerful analgesic effects in the abdominal constriction test (ED 50  = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED 50  = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED 50  = 0.30 mg/kg, in mice). The contributions of MOR and σ 1 R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ 1 R agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects-including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion-than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σ 1 R ligands as a promising avenue for the development of potent and safe analgesics., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Here, we describe the optimization, synthesis, and associated pharmacological analgesic activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor (σ 1 R) antagonists and mu opioid receptor (MOR) agonists. The new compounds were evaluated in vitro in σ 1 R and MOR binding assays. The most promising compound 114 (also called HKC-126), showed superior affinities for σ 1 R and MOR and good selectivity to additional receptors related to pain. Compound 114 showed powerful dose-dependent analgesic effects in the acetic acid writhing test, formalin test, hot plate test, and chronic constriction injury (CCI) neuropathic pain model. In contrast to an equianalgesic dose of fentanyl, compound 114 produced fewer opioid-like side effects, such as reward liability, respiratory depression, physical dependence, and sedation. Lastly, the pharmacokinetic properties of this drug were also acceptable, and these results suggest that compound 114, as a mixed σ 1 R/MOR ligand, has potential 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 © 2021 Elsevier Masson SAS. All rights reserved.)

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.)