Fentanyl is the prototype of the 4-anilidopiperidine class of synthetic opioid analgesics. This study was aimed to review the structure-activity-relationship (SAR) of fentanyl analogs substituted in the position 3, or 4 of the piperidine ring. Pharmacological results show that the groups in position 3 of the piperidine ring, which are larger than methyl, severely reduce the analgesic potency compared to fentanyl. It is likely that the steric factor alone (i.e. voluminosity of the group and cis/trans isomerism), rather than the polarity and/or chemical reactivity, plays a crucial role in the analgesic potency of this series. Although the duration of action, in general, does not depend on the stereochemistry, longer action of the most potent 3-alkyl fentanyl analogs such as cis-3-methyl- and cis-3-ethyl fentanyl, is more likely influenced by pharmacodynamic, rather than pharmacokinetic variables. Also, it is possible that the introduction of a functional group such as 3-carbomethoxy reduces the duration of action by altering pharmacokinetic properties. SAR findings obtained by evaluating the neurotoxic effects of fentanyl analogs substituted in the position 3 of the piperidine ring parallel the SAR findings on analgesia in regard to potency and duration of action. This might suggest that similar receptors are involved in producing both antinociceptive and neurotoxic effects of these drugs. It appears that both the potency and the duration of action in the series of fentanyl analogs substituted in position 4 of the piperidine ring is influenced only by the steric requirement and not by the chemical nature of the substituent.

In many animal species, as well as in humans, high doses of fentanyl (F) produce marked neurotoxic effects, such as muscular rigidity and respiratory depression. The antinociception (hot-plate test), impairment of motor coordination (rotarod test) and acute toxicity of intraperitoneal newly synthesized analogs, (±)cis-3-carbomethoxy- fentanyl (C) and (±)trans-3-carbomethoxyfentanyl (T) were evaluated in mice. The compounds tested induced antinociception, impairment of performance on the rotarod, and lethality in a dose-dependent manner. The relative order of antinociceptive potency was similar to motor impairment potency, as well as lethality: F > C > T. Naloxone hydrochloride (1 mg/kg; sc) abolished all the effects observed, suggesting that they are mediated via opioid receptors, most probably of m type. There were no significant differences between the therapeutic indices of F, C and T. It is concluded, the introduction of 3-carbomethoxy group in the piperidine ring of the fentanyl skeleton reduced the potency, but did not affect tolerability and safety of the compound.

An efficient, five-step synthetic approach to various acyclic 1,3-diamines has been developed and applied to the preparation of a novel class of open-chained fentanyl analogues. The acyclic derivatives 5.1?5.5 (all new compounds) were synthesized with the aim of estimating the significance of the piperidine ring for the opioid analgesic activity of anilido-piperidines. The starting ?-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methylphenethylamine, (93 % yield), was successively reacted with NaH and BuLi, to form the highly reactive ?,?-dienolate anion 1.1a. Regio and chemoselective ?-alkylation of the dienolate with various primary and secondary alkyl halides furnished the ?-keto-amides 1.2?1.5 (76?91 %). Reductive amination of the keto-amides 1.1?1.5 with aniline and Zn powder in acetic acid, via the enamine intermediates 2.1?2.5, afforded the ?-anilino amides 3.1?3.5 (74?85 %). After reductive deoxygenation of the tertiary amide group, using in situ generated diborane, the corresponding 1,3-diamines 4.1?4.5 were obtained (87?97 %). The synthesis of (?)-2,3-seco-fentanyls 5.1?5.5 was completed by N-acylation of the diamines 4.1?4.5 with propionyl chloride, followed by precipitation of the monooxalate salts (86?95 %). The parent compound, 2,3-seco-fentanyl 5.1, was found to be a 40 times less potent narcotic analgesic than fentanyl but still 5?6 times more active than morphine in rats, while i-Pr derivative 5.3 was inactive. Apart from the pharmacological significance, the general procedure described herein may afford various functionalized, 1,3-diamines as potential complexing agents and building blocks for the synthesis of aza-crown ethers.

Brojni rezultati velikih studija pokazuju znacajnu ulogu NO u kaskadi dogadjaja koji dovode do smrti dopaminergickih neurona. Zna se da MPTP uzrokuje neurotoksicnost putem NO sintetisanog pomocu nNOS, ostecujuci primarno dopaminergicka vlakna i zavrsetke u strijatumu, dok NO stvoren uz pomoc iNOS deluje prvenstveno na tela dopaminergickih neurona u pars compacta substantia nigra. Ostecenje uzrokovano NO iz nNOS moze sluziti kao katalizator aktivacije iNOS i glioze. Slican sled dogadjaja moze se primeniti na ostecenje dopaminergickih neurona kod ljudi, bilo usled idiopatske PB ili usled intoksikacije MPTP. Znacaj ovih otkrica je ne samo u osvetljavanju cinioca koji ucestvuju u progresiji neurodegeneracije i PB vec i u upucivanju na nove terapijske mogucnosti.