Synthesis and Biological Evaluation of Metamorphine: A Morphine-Metamizole Adduct from Patient-Controlled Analgesia Pumps.

Opioids are among the most effective drugs in managing moderate to severe pain. Herein, we describe a morphine-metamizole adduct with a phenazone moiety added at position C2 of the morphinan backbone. This adduct, coined metamorphine, was first detected as a byproduct of the morphine-metamizole drug interaction in patient-controlled analgesia (PCA) pumps used for management of severe pain. In this study, metamorphine was successfully synthesized using the Mannich condensation. Qualitative high-performance liquid chromatography with ultraviolet detection (HPLC-UV) analysis was employed to confirm the identity of metamorphine, and the yield was then purified using preparative HPLC. Subsequent studies were undertaken to investigate the pharmacological properties of the newly synthesized compound. A radioligand-based binding assay demonstrated that metamorphine binds strongly to the μ-opioid receptor ( = 3.0 nM). Functional assays showed that it activates both G-protein and β-arrestin pathways, with EC values of 0.169 and 3.06 μM, respectively. However, metamorphine did not exhibit significant activity on TNF, suggesting that it may lack analgesic, antipyretic, and anti-inflammatory effects associated with this pathway. Based on our findings, PCA pumps should be closely monitored, while therapeutic drug monitoring can be utilized to measure metamorphine serum concentration alongside with other opioids. Lead optimization of metamorphine could potentially result in new opioids with an expanded pharmacological spectrum and/or reduced side effects.