Novel sigma 1-antagonists with cis-(+)-normetazocine scaffold: synthesis, molecular modeling, and antinociceptive effect†

Abstract

Inflammatory pain represents one of the unmet clinical needs for patients, as conventional therapies cause several side effects. Recently, new targets involved in inflammatory pain modulation have been identified, including the sigma-1 receptor (σ1R). Selective σ1R antagonists have demonstrated analgesic efficacy in acute and chronic inflammatory pain models. Considering these findings, a series of novel N-normetazocine derivatives has been designed and synthesized to investigate the pivotal role of N-normetazocine stereochemistry in their pharmacological fingerprint. The affinity profile of new ligands versus sigma receptors and opioid receptors was evaluated in vitro, and compound 7 showed a relevant σ1R affinity, with K_iσ1 = 27.5 ± 8.1 nM, and selectivity over sigma-2 receptor (σ2R) and opioid receptors. Furthermore, in vivo, compound 7 significantly reduced inflammatory pain in the second phase of the formalin test. Molecular modeling studies were also performed to analyze the binding mode and the key interactions between the new ligands and σ1R.