Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) and its related compounds: Novel metabolites in rat urine following injection of α-methylfentanyl, one of the most abused typical designer drugs

Abstract

Although 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) is controlled by drug control laws, its slightly modified compounds, which show the same analgesic activities, cannot be controlled legally. Among these fentanyl analogues, 1-[2-(2-methylphenethyl)]-4-(N-propionylanilino)piperidine (α-methylfentanyl) is the typical and most widely abused drug and its overdose has caused a number of fatalities. Analysis of the urine of addicts has been widely performed to detect its metabolites and the unchanged compound for proof of its abuse. In this case, the metabolites detected in urine should reflect the structure of the original compound. In the present report, for clarification of α-methylfentanyl abuse, four novel metabolites, which reflect the original structure of α-methylfentanyl, were identified in rat urine. One of these was the p-hydroxy form of the aromatic ring of the α-methylfentanyl phenethyl group (mono-aromatic hydroxy α-methylfentanyl), while the second and third ones were metabolites of ω-1 or ω position hydroxypropionyl of α-methylfentanyl (mono-hydroxypropionyl α-methylfentanyl). The fourth one was a metabolite involving the p-hydroxy form of the aromatic ring of the phenethyl group and ω position of hydroxypropionyl α-methylfentanyl (di-hydroxy α-methylfentanyl). The structures of these compounds were identified by comparisons of their retention times and mass spectra obtained by gas chromatography-mass spectrometry (GC/MS) and mass chromatography of mono- and di-hydroxy α-methylfentanyl with those of the synthesized authentic compounds.