Eleven chemically modified 1-(2-phenethyl)-4-(N-propionylanilino)-piperidine (fentanyl) analogues were synthesized and their analgesic activities were evaluated by the acetic acid writhing method in mice. Their effective dose (ED50) and lethal dose (LD50) values were compared with those of morphine and fentanyl. The synthesized fentanyl analogues were categorized into three groups: a mono-methylated group, a group in which hydrogen in the para-position of the aromatic ring bound to the propionylanilino group was substituted with F, Cl, CH3, or OCH3, and a group in which the propionyl moiety was changed to an acetyl one. 3-Methylfentanyl showed the strongest analgesic activity among these compounds, and the most frequently abused fentanyl derivative, α-methylfentanyl, also showed quite strong activity. The analgesic activities of p-fluorofentanyl and acetylfentanyl were also relatively strong and not negligible. The activities of other analogues were significantly lower than that of fentanyl. The ranges between LD50 and ED50 of these fentanyl analogues were narrower than that of fentanyl. A number of fatal cases in humans caused by the abuse of fentanyl analogues are considered to be due not only to overdosing but also to the narrow ranges between the ED50 and LD50 values.
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Higashikawa, Y., Suzuki, S. Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) and its related compounds. VI. Structure-analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other analogues. Forensic Toxicol 26, 1–5 (2008). https://doi.org/10.1007/s11419-007-0039-1
- Analgesic activity
- Designer drug