Synthesis of Fentanyl Triazole Derivatives and their Affinity for Mu-Opioid and Sigma-1 Receptors

The search for compounds with affinity for both mu-opioid receptor (MOR) and sigma-1 receptor (σ1R) is one of the innovative directions to develop painkillers with reduced side effects. Additionally, triazole scaffolds have been extensively explored in the last two decades in medicinal chemistry. In this context, we synthesized a series of new triazole fentanyl derivatives and evaluated their affinity for both MOR and σ1R. The binding affinity of the compounds for human MOR was determined in competitive radioligand binding assays, using fentanyl as standard. For the assays with σ1R, a σ1R agonist (SKF10047) was employed. The most active analogue was 6d which moderately binds to MOR with half-maximal inhibitory concentrations (IC₅₀) = 1.9 µM and to σ1R with IC₅₀ = 6.9 µM. Molecular docking calculations were carried out, providing a structural elucidation for the observed values of affinity. Absorption, distribution, metabolism, and excretion toxicity (ADMET) parameters for the new compounds were simulated with the SwissADME tool.

Keywords:
opioids; MOR; sigma-1 receptor; fentanyl; triazole ring