Optimization of bifunctional piperidinamide derivatives as σ₁R Antagonists/MOR agonists for treating neuropathic pain

Here, we describe the optimization, synthesis, and associated pharmacological analgesic activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor (σ₁R) antagonists and mu opioid receptor (MOR) agonists. The new compounds were evaluated in vitro in σ₁R and MOR binding assays. The most promising compound 114 (also called HKC-126), showed superior affinities for σ₁R 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 σ₁R/MOR ligand, has potential for treating neuropathic pain.