3-alkyl fentanyl analogues: Structure-activity-relationship study

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Vučković, Sonja ; Savić-Vujović, Katarina ; Srebro, Dragana ; Ivanović, Milovan ; Došen-Mićović, Ljiljana ; Stojanović, Radan ; Prostran, Milica (2012)
  • Journal: Engrami (issn: 0351-2665)
  • Subject: fentanyl | analogues | structure-activity-relationship(SAR) | analgesic activity

Introduction. Fentanyl belongs to 4-anilidopiperidine class of synthetic opioid analgesics. It is characterized by high potency, rapid onset and short duration of action. A large number of fentanyl analogues have been synthesized so far, both to establish the structure-activity-relationship (SAR) and to find novel, clinically useful analgesic drugs. Objective. In this study, newly synthesized 3-alkyl fentanyl analogues were examined for analgesic activity and compared with fentanyl. Methods. Analgesic activity was assessed by tail-immersion test in rats. Results. The relative potency was: (±)cis-3-methyl fentanyl (8) > (±)trans-3-methyl fentanyl (2) $ (±)cis-3-ethyl fentanyl (1.5) > fentanyl (1) $ (±)trans-3-ethyl fentanyl (0.9) > (±)cis-3-butyl fentanyl (0.064) $ (±)trans-3-butyl fentanyl (0.035) > (±)cis-3-benzyl fentanyl (0.008) $ (±)trans-3-benzyl fentanyl (0.0055). (±)Cis-3-iso-propyl fentanyl, and (±)cis-3-phenethyl fentanyl are inactive in doses up to 5 mg/kg. The duration of action (ED99) was: (±)cis-3-methyl fentanyl (90 min) > (±)trans-3-methyl fentanyl (40 min) # (±)cis-3-ethyl fentanyl (60 min) $ (±)trans-3-ethyl fentanyl (40 min) # fentanyl (50 min) = (±)cis-3-butyl fentanyl (50 min) = (±)trans-3-butyl fentanyl (50 min) = (±)cis-3-benzyl fentanyl (50 min) = (±)trans-3-benzyl fentanyl (50 min). Symbols > and < denotes p<0.05. Conclusion. It is concluded that the analgesic potency of 3-alkyl fentanyl analogues is influenced by the steric factor (voluminosity of the group at the position 3 of the piperidine ring and the cis/trans isomerism). Otherwise, with the exception of 3-methyl fentanyl, the duration of action of 3-alkyl fentanyl analogues is not significantly affected by the stereochemistry.
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