Design,Synthesis And Evaluation Of Fentanyl Analogues

The treatment of severe pain relies heavily upon opioid analgesics,such as morphine,fentanyl and pethidine.Aside from the analgesic effect,morphine and other related analgesics produce a number of side effects after long-term adiministration,including tolerance,physical dependence and respiratory depression.Morden pharmacological studies have suggested that an opioid ligand with a mixed ?-opioid agonist/8-opioid antagonist could be an analgesic with low propensity to produce analgesic tolerance and physical dependence.The structure-activity relationship of emdormorphin(EM)have shown that introduction of alkyl group to the aromatic side chain in position 1 and position 3 of EM results 8-receptor antagonist while reserves ?-receptor agonist of EM.Fentanyl is a frequently-used analgesia agent which acts via ?-opioid receptors.With two benzene in the structure,fentanyl has certain structural similarity with EM.Therefore,based on the understanding of the induction of ?-receptor antagonist by introducing alkyl to the aromatic side chain in position 1 and position 3 of EM,we have synthesized 12 fentanyl analogues by introducing alkyl group to two benzene rings independently or simultaneously.Bioassay indicated that most of the newly synthesized compounds showed potent ?-receptor agonism,and the activity of p,-receptor agonism is better than?-receptor agonism,some other compounds showed potent ?-receptor antagonism,such compounds are expected to have a lower tolerance and dependence.