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 (sigma R-1) antagonists and mu opioid receptor (MOR) agonists. The new compounds were evaluated in vitro in sigma R-1 and MOR binding assays. The most promising compound 114 (also called HKC-126), showed superior affinities for sigma R-1 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 sigma R-1/MOR ligand, has potential for treating neuropathic pain. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

This study describes the optimization, synthesis, and pharmacological activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor antagonists and mu opioid receptor agonists. Compound 114 showed promising affinity and selectivity, with powerful dose-dependent analgesic effects and reduced opioid-like side effects compared to fentanyl. The pharmacokinetic properties of compound 114 were acceptable, suggesting its potential in treating neuropathic pain.