TY  - JOUR
AU  - Vuckovic, S.
AU  - Prostran, M.
AU  - Ivanović, Milovan
AU  - Došen-Mićović, Ljiljana
AU  - Savic Vujovic, K.
AU  - Vucetic, C.
AU  - Kadija, M.
AU  - Mikovic, Z.
PY  - 2011
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/106
AB  - 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 dosedependent manner. The relative order of antinociceptive potency was similar to motor impairment potency, as well as lethality: F  gt  C  gt  T. Naloxone hydrochloride (1 mg/kg; sc) abolished all the effects observed, suggesting that they are mediated via opioid receptors, most probably of μ 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. © 2011 by the authors.
T2  - Pharmaceuticals
T1  - Pharmacological evaluation of 3-carbomethoxy fentanyl in mice
VL  - 4
IS  - 2
SP  - 233
EP  - 243
DO  - 10.3390/ph4020233
ER  - 

@article{
author = "Vuckovic, S. and Prostran, M. and Ivanović, Milovan and Došen-Mićović, Ljiljana and Savic Vujovic, K. and Vucetic, C. and Kadija, M. and Mikovic, Z.",
year = "2011",
abstract = "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 dosedependent manner. The relative order of antinociceptive potency was similar to motor impairment potency, as well as lethality: F  gt  C  gt  T. Naloxone hydrochloride (1 mg/kg; sc) abolished all the effects observed, suggesting that they are mediated via opioid receptors, most probably of μ 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. © 2011 by the authors.",
journal = "Pharmaceuticals",
title = "Pharmacological evaluation of 3-carbomethoxy fentanyl in mice",
volume = "4",
number = "2",
pages = "233-243",
doi = "10.3390/ph4020233"
}

Vuckovic, S., Prostran, M., Ivanović, M., Došen-Mićović, L., Savic Vujovic, K., Vucetic, C., Kadija, M.,& Mikovic, Z.. (2011). Pharmacological evaluation of 3-carbomethoxy fentanyl in mice. in Pharmaceuticals, 4(2), 233-243.
https://doi.org/10.3390/ph4020233

Vuckovic S, Prostran M, Ivanović M, Došen-Mićović L, Savic Vujovic K, Vucetic C, Kadija M, Mikovic Z. Pharmacological evaluation of 3-carbomethoxy fentanyl in mice. in Pharmaceuticals. 2011;4(2):233-243.
doi:10.3390/ph4020233 .

Vuckovic, S., Prostran, M., Ivanović, Milovan, Došen-Mićović, Ljiljana, Savic Vujovic, K., Vucetic, C., Kadija, M., Mikovic, Z., "Pharmacological evaluation of 3-carbomethoxy fentanyl in mice" in Pharmaceuticals, 4, no. 2 (2011):233-243,
https://doi.org/10.3390/ph4020233 . .

TY  - JOUR
AU  - Vuckovic, S.
AU  - Prostran, M.
AU  - Ivanović, Milovan
AU  - Došen-Mićović, Ljiljana
AU  - Todorović, Zoran B.
AU  - Nesic, Z.
AU  - Stojanović, R.
AU  - Divac, N.
AU  - Mikovic, Z.
PY  - 2009
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/999
AB  - 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.
PB  - Bentham Science Publ Ltd, Sharjah
T2  - Current Medicinal Chemistry
T1  - Fentanyl Analogs: Structure-Activity-Relationship Study
VL  - 16
IS  - 19
SP  - 2468
EP  - 2474
DO  - 10.2174/092986709788682074
ER  - 

@article{
author = "Vuckovic, S. and Prostran, M. and Ivanović, Milovan and Došen-Mićović, Ljiljana and Todorović, Zoran B. and Nesic, Z. and Stojanović, R. and Divac, N. and Mikovic, Z.",
year = "2009",
abstract = "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.",
publisher = "Bentham Science Publ Ltd, Sharjah",
journal = "Current Medicinal Chemistry",
title = "Fentanyl Analogs: Structure-Activity-Relationship Study",
volume = "16",
number = "19",
pages = "2468-2474",
doi = "10.2174/092986709788682074"
}

Vuckovic, S., Prostran, M., Ivanović, M., Došen-Mićović, L., Todorović, Z. B., Nesic, Z., Stojanović, R., Divac, N.,& Mikovic, Z.. (2009). Fentanyl Analogs: Structure-Activity-Relationship Study. in Current Medicinal Chemistry
Bentham Science Publ Ltd, Sharjah., 16(19), 2468-2474.
https://doi.org/10.2174/092986709788682074

Vuckovic S, Prostran M, Ivanović M, Došen-Mićović L, Todorović ZB, Nesic Z, Stojanović R, Divac N, Mikovic Z. Fentanyl Analogs: Structure-Activity-Relationship Study. in Current Medicinal Chemistry. 2009;16(19):2468-2474.
doi:10.2174/092986709788682074 .

Vuckovic, S., Prostran, M., Ivanović, Milovan, Došen-Mićović, Ljiljana, Todorović, Zoran B., Nesic, Z., Stojanović, R., Divac, N., Mikovic, Z., "Fentanyl Analogs: Structure-Activity-Relationship Study" in Current Medicinal Chemistry, 16, no. 19 (2009):2468-2474,
https://doi.org/10.2174/092986709788682074 . .

TY  - JOUR
AU  - Ivanović, Milovan
AU  - Mićović, Ivan V.
AU  - Vuckovic, S
AU  - Prostran, M
AU  - Todorović, Zoran B.
AU  - Kiricojevic, VD
AU  - Popović-Đorđević, Jelena
AU  - Došen-Mićović, Ljiljana
PY  - 2004
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/650
AB  - A general five step method for the synthesis of 3-alkylfentanyl analogues (i.e. cis and trans 3-alkyl-4-anilidopiperidines 6.1-6.6) has been developed, The starting N-phenethyl-4-piperidone 1 was first converted into the cyclohexylimine derivative 2. alpha-deprotonated with butyllithium and die resulting imine anion efficiently monoalkylated with primary, and secondary alkyl halides. After mild acid hydrolysis. the obtained 3-alkyl-4-piperidones 3.1-3.6 were isolated in good yields (79-85%), then condensed with aniline to form imines 4.1-4.6. Subsequent reduction of the imines (LiAlH4/THF) yielded cis/trans mixtures of 3-alkyl-4-anilinopiperidines 5.1-5.6. Quantitative separation of the diastereoisomers by column chromatography of Al2O3 gave pure cis 5.1-5.6 (29-51% yield) and trans 5.1-5.6 (19-27% yield), with the cis/trans ratio in the range 7/3-6/4 . The synthesis was concluded by N-acylation of the purified 5.1-5.6, with propionyl chloride, to afford cis and trans 3-alkyl-4-anilidopiperidines 6.1-6.6 (approximate to 95% yield, as monooxalate salts). No enatioseparation was attempted at any stage. The relative cis/trans stereochemistry was provisionally assigned from the H-1-NMR spectra. Of the twelve synthesized 3-alkylfentanyls. ten compounds (two known and eight novel derivatives, all as the monooxalate salts) were preliminarily tested as analgesics in rats, comparing the potency to fentanyl. Except for the known (+/-)-cis-3-Me fentanyl 6.1cis. (8 x fentanyl), and the novel (+/-)-cis-3-Et fentanyl 6.2cis. (1.5 x fentanyl), all of the others were less active than fentanyl or inactive. Some tentative conclusions on the structure-activity relationship (SAR) in this series of derivatives have been made.
AB  - Razvijen je opšti metod za sintezu 3-alkil analoga fentanila (tj. cis i trans 3-alkil-4-anilidopiperidina 6.1–6.6) u pet faza. Polazni N-fenetil-4-piperidon 1 prvo je preveden u cikloheksiliminski derivat 2, α-deprotonovan butillitijumom, a postali iminski anjon efikasno monoalkilovan primarnim i sekundarnim alkilhalogenidima. Posle blage kisele hidrolize, nastali 3-alkil-4-piperidoni 3.1–3.6 izolovani su u dobrim prinosima (79–85 %), zatim kondenzovani sa anilinom do imina 4.1–4.6. Redukcijom ovih imina (LiAlH4/THF) dobijene su cis/trans smese 3-alkil-4-anilinopiperidina 5.1–5.6. Kvantitativnim hromatografskim razdvajanjem dijastereoizomera na stubu Al2O3 izolovani su čisti cis 5.1–5.6 (prinos 29–51 %) i trans 5.1–5.6 (prinos 19–27 %), gde je cis/trans odnos bio u opsegu 7/3–6/4. Sinteza je završena N-acilovanjem prečišćenih intermedijera 5.1–5.6 pomoću propionil-hlorida, pri čemu su postali cis i trans 3-alkil-4-anilidopiperidini 6.1–6.6 (prinos _ 95 %, kao monooksalatne soli). Ni u jednoj fazi nije pokušano razdvajanje enantiomera. Relativna, cis/trans, stereohemija preliminarno je određena iz 1H-NMRspektra. Od dvanaest sintetisanih 3-alkil-fentanila, deset jedinjenja (dva poznata i osam novih, sva u obliku monookasalatnih soli) preliminarno su testirana kao analgetici na pacovima, poredeći aktivnost sa fentanilom.Osim poznatog (±)-cis-3-Me fentanila 6.1 cis, (8 x fentanil), i novog (±)-cis-3-Et fentanila 6.2 cis, (1,5 x fentanil), svi ostali bili su manje aktivni ili neaktivni. Izvedeni su određeni, preliminarni zaključci u vezi odnosa strukture i aktivnosti u ovoj seriji derivata.
PB  - Serbian Chemical Soc, Belgrade
T2  - Journal of the Serbian Chemical Society
T1  - The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues
T1  - Sinteza i preliminarni farmakološki testovi recemskih cis i trans 3-alkilanaloga fentanila
VL  - 69
IS  - 7
SP  - 511
EP  - 526
DO  - 10.2298/JSC0407511I
ER  - 

@article{
author = "Ivanović, Milovan and Mićović, Ivan V. and Vuckovic, S and Prostran, M and Todorović, Zoran B. and Kiricojevic, VD and Popović-Đorđević, Jelena and Došen-Mićović, Ljiljana",
year = "2004",
abstract = "A general five step method for the synthesis of 3-alkylfentanyl analogues (i.e. cis and trans 3-alkyl-4-anilidopiperidines 6.1-6.6) has been developed, The starting N-phenethyl-4-piperidone 1 was first converted into the cyclohexylimine derivative 2. alpha-deprotonated with butyllithium and die resulting imine anion efficiently monoalkylated with primary, and secondary alkyl halides. After mild acid hydrolysis. the obtained 3-alkyl-4-piperidones 3.1-3.6 were isolated in good yields (79-85%), then condensed with aniline to form imines 4.1-4.6. Subsequent reduction of the imines (LiAlH4/THF) yielded cis/trans mixtures of 3-alkyl-4-anilinopiperidines 5.1-5.6. Quantitative separation of the diastereoisomers by column chromatography of Al2O3 gave pure cis 5.1-5.6 (29-51% yield) and trans 5.1-5.6 (19-27% yield), with the cis/trans ratio in the range 7/3-6/4 . The synthesis was concluded by N-acylation of the purified 5.1-5.6, with propionyl chloride, to afford cis and trans 3-alkyl-4-anilidopiperidines 6.1-6.6 (approximate to 95% yield, as monooxalate salts). No enatioseparation was attempted at any stage. The relative cis/trans stereochemistry was provisionally assigned from the H-1-NMR spectra. Of the twelve synthesized 3-alkylfentanyls. ten compounds (two known and eight novel derivatives, all as the monooxalate salts) were preliminarily tested as analgesics in rats, comparing the potency to fentanyl. Except for the known (+/-)-cis-3-Me fentanyl 6.1cis. (8 x fentanyl), and the novel (+/-)-cis-3-Et fentanyl 6.2cis. (1.5 x fentanyl), all of the others were less active than fentanyl or inactive. Some tentative conclusions on the structure-activity relationship (SAR) in this series of derivatives have been made., Razvijen je opšti metod za sintezu 3-alkil analoga fentanila (tj. cis i trans 3-alkil-4-anilidopiperidina 6.1–6.6) u pet faza. Polazni N-fenetil-4-piperidon 1 prvo je preveden u cikloheksiliminski derivat 2, α-deprotonovan butillitijumom, a postali iminski anjon efikasno monoalkilovan primarnim i sekundarnim alkilhalogenidima. Posle blage kisele hidrolize, nastali 3-alkil-4-piperidoni 3.1–3.6 izolovani su u dobrim prinosima (79–85 %), zatim kondenzovani sa anilinom do imina 4.1–4.6. Redukcijom ovih imina (LiAlH4/THF) dobijene su cis/trans smese 3-alkil-4-anilinopiperidina 5.1–5.6. Kvantitativnim hromatografskim razdvajanjem dijastereoizomera na stubu Al2O3 izolovani su čisti cis 5.1–5.6 (prinos 29–51 %) i trans 5.1–5.6 (prinos 19–27 %), gde je cis/trans odnos bio u opsegu 7/3–6/4. Sinteza je završena N-acilovanjem prečišćenih intermedijera 5.1–5.6 pomoću propionil-hlorida, pri čemu su postali cis i trans 3-alkil-4-anilidopiperidini 6.1–6.6 (prinos _ 95 %, kao monooksalatne soli). Ni u jednoj fazi nije pokušano razdvajanje enantiomera. Relativna, cis/trans, stereohemija preliminarno je određena iz 1H-NMRspektra. Od dvanaest sintetisanih 3-alkil-fentanila, deset jedinjenja (dva poznata i osam novih, sva u obliku monookasalatnih soli) preliminarno su testirana kao analgetici na pacovima, poredeći aktivnost sa fentanilom.Osim poznatog (±)-cis-3-Me fentanila 6.1 cis, (8 x fentanil), i novog (±)-cis-3-Et fentanila 6.2 cis, (1,5 x fentanil), svi ostali bili su manje aktivni ili neaktivni. Izvedeni su određeni, preliminarni zaključci u vezi odnosa strukture i aktivnosti u ovoj seriji derivata.",
publisher = "Serbian Chemical Soc, Belgrade",
journal = "Journal of the Serbian Chemical Society",
title = "The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues, Sinteza i preliminarni farmakološki testovi recemskih cis i trans 3-alkilanaloga fentanila",
volume = "69",
number = "7",
pages = "511-526",
doi = "10.2298/JSC0407511I"
}

Ivanović, M., Mićović, I. V., Vuckovic, S., Prostran, M., Todorović, Z. B., Kiricojevic, V., Popović-Đorđević, J.,& Došen-Mićović, L.. (2004). The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues. in Journal of the Serbian Chemical Society
Serbian Chemical Soc, Belgrade., 69(7), 511-526.
https://doi.org/10.2298/JSC0407511I

Ivanović M, Mićović IV, Vuckovic S, Prostran M, Todorović ZB, Kiricojevic V, Popović-Đorđević J, Došen-Mićović L. The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues. in Journal of the Serbian Chemical Society. 2004;69(7):511-526.
doi:10.2298/JSC0407511I .

Ivanović, Milovan, Mićović, Ivan V., Vuckovic, S, Prostran, M, Todorović, Zoran B., Kiricojevic, VD, Popović-Đorđević, Jelena, Došen-Mićović, Ljiljana, "The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues" in Journal of the Serbian Chemical Society, 69, no. 7 (2004):511-526,
https://doi.org/10.2298/JSC0407511I . .

TY  - JOUR
AU  - Ivanović, Milovan
AU  - Mićović, Ivan V.
AU  - Vuckovic, S
AU  - Prostran, M
AU  - Todorović, Zoran B.
AU  - Ivanovic, ER
AU  - Kiricojevic, VD
AU  - Popović-Đorđević, Jelena
AU  - Došen-Mićović, Ljiljana
PY  - 2004
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/681
AB  - 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 beta-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methyl phenethylamine, (93% yield), was successively reacted with NaH and BuLi, to form the highly reactive alpha,gamma-dienolate anion 1.1a. Regio and chemoselective gamma-alkylation of the dienolate with various primary and secondary alkyl halides furnished the beta-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 beta-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.
AB  - Razvijen je efikasan postupak za dobijanje različitih acikličnih 1,3-diamina u pet faza, i primenjen u sintezi nove klase analoga fentanila otvorenog niza. Derivati 5.1–5.5 (svi su nova jedinjenja) sintetisani su sa ciljem da se proceni uticaj piperidinskog prstena na opioidnoanalgetičku aktivnost anilido-piperidina. Polazni β-keto-amid 1.1, dobijen aminolizom metilacetoacetata metilfenetilaminom (prinos 93 %), bio je sukcesivno tretiran sa NaH i BuLi, pri čemu je postao veoma reaktivni α,γ-dienolatni anjon 1.1a. Regio- i hemoselektivnim γ-alkilovanjem ovog dienolata različitim primarnim i sekundarnim alkil-halogenidima, dobijeni su β-keto-amidi 1.2–1.5 (prinos 76–91 %). Reduktivnim aminovanjem keto-amida 1.1–1.5 pomoću Zn praha i sirćetne kiseline, preko enaminskih intermedijera 2.1–2.5, postali su -anilino-amidi 3.1–3.5 (prinos 74–85 %). Posle reduktivne deoksigenacije tercijene amidne funkcije, koristeći in situ generisani diboran, odgovarajući 1,3-diamini 4.1–4.5 izolovani su u prinosima 87–97 %. Sinteza (±)-2,3-seco-fentanila 5.1–5.5 završena je N-acilovanjem diamina 4.1–4.5 propionil-hloridom, a zatim taloženjem u obliku monooksalatnih soli (prinos 86–95 %). Nađeno je da je osnovno jedinjenje, 2,3-seco fentanil 5.1, 40 puta slabiji narkotički analgetik od fentanila, ali još uvek 5–6 puta aktivniji od morfina u pacova, dok je i-Pr derivat 5.3 bio neaktivan. Osim farmakološkog značaja, opštim postupkom prikazanim u ovom radu, mogu se sintetisati različiti 1,3-diamini, uključujući i one sa funkcionalnim grupama. Ova jedinjenja mogu biti potencijalno značajna kao kompleksirajući agensi i kao intermedijeri u sintezi aza-kraun-etara.
PB  - Serbian Chemical Soc, Belgrade
T2  - Journal of the Serbian Chemical Society
T1  - The synthesis and pharmacological evaluation of (+/-)-2,3-seco-fentanyl analogues
T1  - Sinteza i farmakološko ispitivanje (±)-2,3-seco-analoga fentanila
VL  - 69
IS  - 11
SP  - 955
EP  - 968
DO  - 10.2298/JSC0411955I
ER  - 

@article{
author = "Ivanović, Milovan and Mićović, Ivan V. and Vuckovic, S and Prostran, M and Todorović, Zoran B. and Ivanovic, ER and Kiricojevic, VD and Popović-Đorđević, Jelena and Došen-Mićović, Ljiljana",
year = "2004",
abstract = "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 beta-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methyl phenethylamine, (93% yield), was successively reacted with NaH and BuLi, to form the highly reactive alpha,gamma-dienolate anion 1.1a. Regio and chemoselective gamma-alkylation of the dienolate with various primary and secondary alkyl halides furnished the beta-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 beta-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., Razvijen je efikasan postupak za dobijanje različitih acikličnih 1,3-diamina u pet faza, i primenjen u sintezi nove klase analoga fentanila otvorenog niza. Derivati 5.1–5.5 (svi su nova jedinjenja) sintetisani su sa ciljem da se proceni uticaj piperidinskog prstena na opioidnoanalgetičku aktivnost anilido-piperidina. Polazni β-keto-amid 1.1, dobijen aminolizom metilacetoacetata metilfenetilaminom (prinos 93 %), bio je sukcesivno tretiran sa NaH i BuLi, pri čemu je postao veoma reaktivni α,γ-dienolatni anjon 1.1a. Regio- i hemoselektivnim γ-alkilovanjem ovog dienolata različitim primarnim i sekundarnim alkil-halogenidima, dobijeni su β-keto-amidi 1.2–1.5 (prinos 76–91 %). Reduktivnim aminovanjem keto-amida 1.1–1.5 pomoću Zn praha i sirćetne kiseline, preko enaminskih intermedijera 2.1–2.5, postali su -anilino-amidi 3.1–3.5 (prinos 74–85 %). Posle reduktivne deoksigenacije tercijene amidne funkcije, koristeći in situ generisani diboran, odgovarajući 1,3-diamini 4.1–4.5 izolovani su u prinosima 87–97 %. Sinteza (±)-2,3-seco-fentanila 5.1–5.5 završena je N-acilovanjem diamina 4.1–4.5 propionil-hloridom, a zatim taloženjem u obliku monooksalatnih soli (prinos 86–95 %). Nađeno je da je osnovno jedinjenje, 2,3-seco fentanil 5.1, 40 puta slabiji narkotički analgetik od fentanila, ali još uvek 5–6 puta aktivniji od morfina u pacova, dok je i-Pr derivat 5.3 bio neaktivan. Osim farmakološkog značaja, opštim postupkom prikazanim u ovom radu, mogu se sintetisati različiti 1,3-diamini, uključujući i one sa funkcionalnim grupama. Ova jedinjenja mogu biti potencijalno značajna kao kompleksirajući agensi i kao intermedijeri u sintezi aza-kraun-etara.",
publisher = "Serbian Chemical Soc, Belgrade",
journal = "Journal of the Serbian Chemical Society",
title = "The synthesis and pharmacological evaluation of (+/-)-2,3-seco-fentanyl analogues, Sinteza i farmakološko ispitivanje (±)-2,3-seco-analoga fentanila",
volume = "69",
number = "11",
pages = "955-968",
doi = "10.2298/JSC0411955I"
}

Ivanović, M., Mićović, I. V., Vuckovic, S., Prostran, M., Todorović, Z. B., Ivanovic, E., Kiricojevic, V., Popović-Đorđević, J.,& Došen-Mićović, L.. (2004). The synthesis and pharmacological evaluation of (+/-)-2,3-seco-fentanyl analogues. in Journal of the Serbian Chemical Society
Serbian Chemical Soc, Belgrade., 69(11), 955-968.
https://doi.org/10.2298/JSC0411955I

Ivanović M, Mićović IV, Vuckovic S, Prostran M, Todorović ZB, Ivanovic E, Kiricojevic V, Popović-Đorđević J, Došen-Mićović L. The synthesis and pharmacological evaluation of (+/-)-2,3-seco-fentanyl analogues. in Journal of the Serbian Chemical Society. 2004;69(11):955-968.
doi:10.2298/JSC0411955I .

Ivanović, Milovan, Mićović, Ivan V., Vuckovic, S, Prostran, M, Todorović, Zoran B., Ivanovic, ER, Kiricojevic, VD, Popović-Đorđević, Jelena, Došen-Mićović, Ljiljana, "The synthesis and pharmacological evaluation of (+/-)-2,3-seco-fentanyl analogues" in Journal of the Serbian Chemical Society, 69, no. 11 (2004):955-968,
https://doi.org/10.2298/JSC0411955I . .

TY  - CONF
AU  - Nesic, Z
AU  - Vuckovic, S
AU  - Prostran, M
AU  - Todorović, Zoran B.
AU  - Stojanović, R.
AU  - Ivanović, Milovan
PY  - 2004
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/671
PB  - Elsevier Science Bv, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Higher ambient temperature, thermoregulatory behaviour, and the cataleptic effect of fentanyl in rats
VL  - 14
DO  - 10.1016/S0924-977X(04)80559-5
ER  - 

@conference{
author = "Nesic, Z and Vuckovic, S and Prostran, M and Todorović, Zoran B. and Stojanović, R. and Ivanović, Milovan",
year = "2004",
publisher = "Elsevier Science Bv, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Higher ambient temperature, thermoregulatory behaviour, and the cataleptic effect of fentanyl in rats",
volume = "14",
doi = "10.1016/S0924-977X(04)80559-5"
}

Nesic, Z., Vuckovic, S., Prostran, M., Todorović, Z. B., Stojanović, R.,& Ivanović, M.. (2004). Higher ambient temperature, thermoregulatory behaviour, and the cataleptic effect of fentanyl in rats. in European Neuropsychopharmacology
Elsevier Science Bv, Amsterdam., 14.
https://doi.org/10.1016/S0924-977X(04)80559-5

Nesic Z, Vuckovic S, Prostran M, Todorović ZB, Stojanović R, Ivanović M. Higher ambient temperature, thermoregulatory behaviour, and the cataleptic effect of fentanyl in rats. in European Neuropsychopharmacology. 2004;14.
doi:10.1016/S0924-977X(04)80559-5 .

Nesic, Z, Vuckovic, S, Prostran, M, Todorović, Zoran B., Stojanović, R., Ivanović, Milovan, "Higher ambient temperature, thermoregulatory behaviour, and the cataleptic effect of fentanyl in rats" in European Neuropsychopharmacology, 14 (2004),
https://doi.org/10.1016/S0924-977X(04)80559-5 . .

TY  - CONF
AU  - Prostran, M
AU  - Nesic, Z
AU  - Vuckovic, S
AU  - Todorović, Zoran B.
AU  - Stojanović, R.
AU  - Ivanović, Milovan
PY  - 2003
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/148
PB  - Elsevier Science Bv, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Acute exposure to higher ambient temperature potentiates cataleptic and hyperthermic effects of fentanyl in female rats
VL  - 13
DO  - 10.1016/S0924-977X(03)92337-6
ER  - 

@conference{
author = "Prostran, M and Nesic, Z and Vuckovic, S and Todorović, Zoran B. and Stojanović, R. and Ivanović, Milovan",
year = "2003",
publisher = "Elsevier Science Bv, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Acute exposure to higher ambient temperature potentiates cataleptic and hyperthermic effects of fentanyl in female rats",
volume = "13",
doi = "10.1016/S0924-977X(03)92337-6"
}

Prostran, M., Nesic, Z., Vuckovic, S., Todorović, Z. B., Stojanović, R.,& Ivanović, M.. (2003). Acute exposure to higher ambient temperature potentiates cataleptic and hyperthermic effects of fentanyl in female rats. in European Neuropsychopharmacology
Elsevier Science Bv, Amsterdam., 13.
https://doi.org/10.1016/S0924-977X(03)92337-6

Prostran M, Nesic Z, Vuckovic S, Todorović ZB, Stojanović R, Ivanović M. Acute exposure to higher ambient temperature potentiates cataleptic and hyperthermic effects of fentanyl in female rats. in European Neuropsychopharmacology. 2003;13.
doi:10.1016/S0924-977X(03)92337-6 .

Prostran, M, Nesic, Z, Vuckovic, S, Todorović, Zoran B., Stojanović, R., Ivanović, Milovan, "Acute exposure to higher ambient temperature potentiates cataleptic and hyperthermic effects of fentanyl in female rats" in European Neuropsychopharmacology, 13 (2003),
https://doi.org/10.1016/S0924-977X(03)92337-6 . .

TY  - CONF
AU  - Vuckovic, S
AU  - Prostran, M
AU  - Ivanović, Milovan
AU  - Todorović, Zoran B.
AU  - Stojanović, R.
AU  - Nesic, Z
PY  - 2001
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/451
PB  - Springer-Verlag, New York
C3  - Naunyn-Schmiedeberg's Archives of Pharmacology
T1  - Antinociceptive activity of 4-methyl fentanyl in rats
VL  - 363
IS  - 4
UR  - https://hdl.handle.net/21.15107/rcub_cherry_451
ER  - 

@conference{
author = "Vuckovic, S and Prostran, M and Ivanović, Milovan and Todorović, Zoran B. and Stojanović, R. and Nesic, Z",
year = "2001",
publisher = "Springer-Verlag, New York",
journal = "Naunyn-Schmiedeberg's Archives of Pharmacology",
title = "Antinociceptive activity of 4-methyl fentanyl in rats",
volume = "363",
number = "4",
url = "https://hdl.handle.net/21.15107/rcub_cherry_451"
}

Vuckovic, S., Prostran, M., Ivanović, M., Todorović, Z. B., Stojanović, R.,& Nesic, Z.. (2001). Antinociceptive activity of 4-methyl fentanyl in rats. in Naunyn-Schmiedeberg's Archives of Pharmacology
Springer-Verlag, New York., 363(4).
https://hdl.handle.net/21.15107/rcub_cherry_451

Vuckovic S, Prostran M, Ivanović M, Todorović ZB, Stojanović R, Nesic Z. Antinociceptive activity of 4-methyl fentanyl in rats. in Naunyn-Schmiedeberg's Archives of Pharmacology. 2001;363(4).
https://hdl.handle.net/21.15107/rcub_cherry_451 .

Vuckovic, S, Prostran, M, Ivanović, Milovan, Todorović, Zoran B., Stojanović, R., Nesic, Z, "Antinociceptive activity of 4-methyl fentanyl in rats" in Naunyn-Schmiedeberg's Archives of Pharmacology, 363, no. 4 (2001),
https://hdl.handle.net/21.15107/rcub_cherry_451 .

TY  - CONF
AU  - Vuckovic, S.
AU  - Prostran, M.
AU  - Nesic, Z.
AU  - Todorović, Zoran B.
AU  - Stojanović, R.
AU  - Ivanović, Milovan
PY  - 2001
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/576
PB  - Wiley-Blackwell, Malden
C3  - Fundamental and Clinical Pharmacology
T1  - Pharmacological evaluation of 3-carbomethoxy fentanyl ('iso-carfentanil') in mice
VL  - 15
SP  - 139
EP  - 139
UR  - https://hdl.handle.net/21.15107/rcub_cherry_576
ER  - 

@conference{
author = "Vuckovic, S. and Prostran, M. and Nesic, Z. and Todorović, Zoran B. and Stojanović, R. and Ivanović, Milovan",
year = "2001",
publisher = "Wiley-Blackwell, Malden",
journal = "Fundamental and Clinical Pharmacology",
title = "Pharmacological evaluation of 3-carbomethoxy fentanyl ('iso-carfentanil') in mice",
volume = "15",
pages = "139-139",
url = "https://hdl.handle.net/21.15107/rcub_cherry_576"
}

Vuckovic, S., Prostran, M., Nesic, Z., Todorović, Z. B., Stojanović, R.,& Ivanović, M.. (2001). Pharmacological evaluation of 3-carbomethoxy fentanyl ('iso-carfentanil') in mice. in Fundamental and Clinical Pharmacology
Wiley-Blackwell, Malden., 15, 139-139.
https://hdl.handle.net/21.15107/rcub_cherry_576

Vuckovic S, Prostran M, Nesic Z, Todorović ZB, Stojanović R, Ivanović M. Pharmacological evaluation of 3-carbomethoxy fentanyl ('iso-carfentanil') in mice. in Fundamental and Clinical Pharmacology. 2001;15:139-139.
https://hdl.handle.net/21.15107/rcub_cherry_576 .

Vuckovic, S., Prostran, M., Nesic, Z., Todorović, Zoran B., Stojanović, R., Ivanović, Milovan, "Pharmacological evaluation of 3-carbomethoxy fentanyl ('iso-carfentanil') in mice" in Fundamental and Clinical Pharmacology, 15 (2001):139-139,
https://hdl.handle.net/21.15107/rcub_cherry_576 .

TY  - JOUR
AU  - Vuckovic, S
AU  - Prostran, M
AU  - Ivanović, Milovan
AU  - Ristovic, Z
AU  - Stojanović, R.
PY  - 2000
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/388
AB  - 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 antinociceptive drugs. In this study, the newly synthesized fentanyl analogue 3-carbomethoxy fentanyl (iso-carfentanil) was compared to fentanyl for its antinociceptive activity (tail-immersion test) in rats. It was revealed that the introduction of a 3-carbomethoxy group in the piperidine ring of fentanyl skeleton reduced the potency and shortened the duration of action of the parent compound, i.e., fentanyl. The antinociceptive potency of 3-carbomethoxy fentanyl is influenced mainly by the steric factor (voluminosity of the carbomethoxy group and the cis/trans isomerism), while the chemical nature of the group is probably irrelevant. This is in agreement with SAR studies of other 3-substituted fentanyl analogues. In contrast to potency, the duration of action is not affected by cis/trans isomerism. It is assumed that the time course of action of 3-carbomethoxy fentanyl is influenced by the nature of the carbomethoxy group. Since the potency and the duration of action of this novel antinociceptive compound are interesting from the aspect of SAR studies and have potential promise for clinical application, 3-carbomethoxy fentanyl deserves to be extensively evaluated.
PB  - Japanese Pharmacological Soc, Kyoto
T2  - Japanese Journal of Pharmacology
T1  - Antinociceptive activity of the novel fentanyl analogue iso-carfentanil in rats
VL  - 84
IS  - 2
SP  - 188
EP  - 195
DO  - 10.1254/jjp.84.188
ER  - 

@article{
author = "Vuckovic, S and Prostran, M and Ivanović, Milovan and Ristovic, Z and Stojanović, R.",
year = "2000",
abstract = "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 antinociceptive drugs. In this study, the newly synthesized fentanyl analogue 3-carbomethoxy fentanyl (iso-carfentanil) was compared to fentanyl for its antinociceptive activity (tail-immersion test) in rats. It was revealed that the introduction of a 3-carbomethoxy group in the piperidine ring of fentanyl skeleton reduced the potency and shortened the duration of action of the parent compound, i.e., fentanyl. The antinociceptive potency of 3-carbomethoxy fentanyl is influenced mainly by the steric factor (voluminosity of the carbomethoxy group and the cis/trans isomerism), while the chemical nature of the group is probably irrelevant. This is in agreement with SAR studies of other 3-substituted fentanyl analogues. In contrast to potency, the duration of action is not affected by cis/trans isomerism. It is assumed that the time course of action of 3-carbomethoxy fentanyl is influenced by the nature of the carbomethoxy group. Since the potency and the duration of action of this novel antinociceptive compound are interesting from the aspect of SAR studies and have potential promise for clinical application, 3-carbomethoxy fentanyl deserves to be extensively evaluated.",
publisher = "Japanese Pharmacological Soc, Kyoto",
journal = "Japanese Journal of Pharmacology",
title = "Antinociceptive activity of the novel fentanyl analogue iso-carfentanil in rats",
volume = "84",
number = "2",
pages = "188-195",
doi = "10.1254/jjp.84.188"
}

Vuckovic, S., Prostran, M., Ivanović, M., Ristovic, Z.,& Stojanović, R.. (2000). Antinociceptive activity of the novel fentanyl analogue iso-carfentanil in rats. in Japanese Journal of Pharmacology
Japanese Pharmacological Soc, Kyoto., 84(2), 188-195.
https://doi.org/10.1254/jjp.84.188

Vuckovic S, Prostran M, Ivanović M, Ristovic Z, Stojanović R. Antinociceptive activity of the novel fentanyl analogue iso-carfentanil in rats. in Japanese Journal of Pharmacology. 2000;84(2):188-195.
doi:10.1254/jjp.84.188 .

Vuckovic, S, Prostran, M, Ivanović, Milovan, Ristovic, Z, Stojanović, R., "Antinociceptive activity of the novel fentanyl analogue iso-carfentanil in rats" in Japanese Journal of Pharmacology, 84, no. 2 (2000):188-195,
https://doi.org/10.1254/jjp.84.188 . .

TY  - JOUR
AU  - Vuckovic, S
AU  - Ivanović, Milovan
AU  - Prostran, M
AU  - Todorović, Zoran B.
AU  - Ristovic, Z
AU  - Micovic, I
AU  - Beleslin, D.
PY  - 1998
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/403
AB  - The influence of higher environmental temperature (HET=30+/-1 degrees C) on fentanyl-induced behavior was studied in unrestrained rats. Subacute exposure (3 days) of rats to HET significantly (P  lt 0.01) increased the cataleptic effect of fentanyl citrate (0.5 mg/kg), in comparison to the corresponding exposure to normal environmental temperature (NET=22+/-1 degrees C). Also, the hyperthermic response of rats to a low dose of fentanyl citrate (0.2-0.5 mg/kg) was significantly (P lt 0.01) potentiated, and the hypothermic response to a high dose of fentanyl citrate (1.5 mg/kg) was significantly (P  lt 0.05) attenuated after exposure to HET. Fentanyl-induced hyperexcitability, loss of righting reflex, loss of corneal reflex and analgesia were not significantly affected by HET. This study provides the first evidence on the influence of environmental temperature on drug-induced catalepsy. MET-induced potentiation of the cataleptic response to fentanyl could be the result of an interference with behavioral thermoregulation.
PB  - Japanese Pharmacological Soc, Kyoto
T2  - Japanese Journal of Pharmacology
T1  - Higher environmental temperature potentiates cataleptic effect of fentanyl in rats
VL  - 78
IS  - 4
SP  - 523
EP  - 527
DO  - 10.1254/jjp.78.523
ER  - 

@article{
author = "Vuckovic, S and Ivanović, Milovan and Prostran, M and Todorović, Zoran B. and Ristovic, Z and Micovic, I and Beleslin, D.",
year = "1998",
abstract = "The influence of higher environmental temperature (HET=30+/-1 degrees C) on fentanyl-induced behavior was studied in unrestrained rats. Subacute exposure (3 days) of rats to HET significantly (P  lt 0.01) increased the cataleptic effect of fentanyl citrate (0.5 mg/kg), in comparison to the corresponding exposure to normal environmental temperature (NET=22+/-1 degrees C). Also, the hyperthermic response of rats to a low dose of fentanyl citrate (0.2-0.5 mg/kg) was significantly (P lt 0.01) potentiated, and the hypothermic response to a high dose of fentanyl citrate (1.5 mg/kg) was significantly (P  lt 0.05) attenuated after exposure to HET. Fentanyl-induced hyperexcitability, loss of righting reflex, loss of corneal reflex and analgesia were not significantly affected by HET. This study provides the first evidence on the influence of environmental temperature on drug-induced catalepsy. MET-induced potentiation of the cataleptic response to fentanyl could be the result of an interference with behavioral thermoregulation.",
publisher = "Japanese Pharmacological Soc, Kyoto",
journal = "Japanese Journal of Pharmacology",
title = "Higher environmental temperature potentiates cataleptic effect of fentanyl in rats",
volume = "78",
number = "4",
pages = "523-527",
doi = "10.1254/jjp.78.523"
}

Vuckovic, S., Ivanović, M., Prostran, M., Todorović, Z. B., Ristovic, Z., Micovic, I.,& Beleslin, D.. (1998). Higher environmental temperature potentiates cataleptic effect of fentanyl in rats. in Japanese Journal of Pharmacology
Japanese Pharmacological Soc, Kyoto., 78(4), 523-527.
https://doi.org/10.1254/jjp.78.523

Vuckovic S, Ivanović M, Prostran M, Todorović ZB, Ristovic Z, Micovic I, Beleslin D. Higher environmental temperature potentiates cataleptic effect of fentanyl in rats. in Japanese Journal of Pharmacology. 1998;78(4):523-527.
doi:10.1254/jjp.78.523 .

Vuckovic, S, Ivanović, Milovan, Prostran, M, Todorović, Zoran B., Ristovic, Z, Micovic, I, Beleslin, D., "Higher environmental temperature potentiates cataleptic effect of fentanyl in rats" in Japanese Journal of Pharmacology, 78, no. 4 (1998):523-527,
https://doi.org/10.1254/jjp.78.523 . .