Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated Pathways

Opioid receptors (ORs) are classified into three types (mu, delta, and kappa), and opioid analgesics are mainly mediated by mu OR activation; however, their use is sometimes restricted by unfavorable effects. The selective kappa OR agonist nalfurafine was initially developed as an analgesic, but its indication was changed because of the narrow safety margin. The activation of ORs mainly induces two intracellular signaling pathways: a G-protein-mediated pathway and a beta-arrestin-mediated pathway. Recently, the expectations for kappa OR analgesics that selectively activate these pathways have increased; however, the structural properties required for the selectivity of nalfurafine are still unknown. Therefore, we evaluated the partial structures of nalfurafine that are necessary for the selectivity of these two pathways. We assayed the properties of nalfurafine and six nalfurafine analogs (SYKs) using cells stably expressing kappa ORs. The SYKs activated kappa ORs in a concentration-dependent manner with higher EC50 values than nalfurafine. Upon bias factor assessment, only SYK-309 (possessing the 3S-hydroxy group) showed higher selectivity of G-protein-mediated signaling activities than nalfurafine, suggesting the direction of the 3S-hydroxy group may affect the beta-arrestin-mediated pathway. In conclusion, nalfurafine analogs having a 3S-hydroxy group, such as SYK-309, could be considered G-protein-biased kappa OR agonists.

Automated summary

This study evaluated the structural requirements for the selectivity of nalfurafine in activating G-protein-mediated and β-arrestin-mediated pathways. The findings suggest that nalfurafine analogs with a 3S-hydroxy group may be G-protein-biased κ OR agonists.