TY  - JOUR
AU  - Jevtić, Ivana I.
AU  - Savić-Vujović, Katarina
AU  - Srebro, Dragana
AU  - Vučković, Sonja M.
AU  - Ivanović, Milovan
AU  - Kostić-Rajačić, Slađana
PY  - 2020
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/4211
AB  - Background: 4-Anilidopiperidine class of synthetic opioid analgesics, with it’s representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of μ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity. Methods: The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test. Results: The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In addition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test. Conclusion: Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.
PB  - Springer
T2  - Pharmacological Reports
T1  - Synthesis and pharmacological evaluation of novel cis and trans 3-substituted anilidopiperidines
VL  - 72
IS  - 4
SP  - 1069
EP  - 1075
DO  - 10.1007/s43440-020-00121-2
ER  - 

@article{
author = "Jevtić, Ivana I. and Savić-Vujović, Katarina and Srebro, Dragana and Vučković, Sonja M. and Ivanović, Milovan and Kostić-Rajačić, Slađana",
year = "2020",
abstract = "Background: 4-Anilidopiperidine class of synthetic opioid analgesics, with it’s representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of μ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity. Methods: The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test. Results: The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In addition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test. Conclusion: Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.",
publisher = "Springer",
journal = "Pharmacological Reports",
title = "Synthesis and pharmacological evaluation of novel cis and trans 3-substituted anilidopiperidines",
volume = "72",
number = "4",
pages = "1069-1075",
doi = "10.1007/s43440-020-00121-2"
}

Jevtić, I. I., Savić-Vujović, K., Srebro, D., Vučković, S. M., Ivanović, M.,& Kostić-Rajačić, S.. (2020). Synthesis and pharmacological evaluation of novel cis and trans 3-substituted anilidopiperidines. in Pharmacological Reports
Springer., 72(4), 1069-1075.
https://doi.org/10.1007/s43440-020-00121-2

Jevtić II, Savić-Vujović K, Srebro D, Vučković SM, Ivanović M, Kostić-Rajačić S. Synthesis and pharmacological evaluation of novel cis and trans 3-substituted anilidopiperidines. in Pharmacological Reports. 2020;72(4):1069-1075.
doi:10.1007/s43440-020-00121-2 .

Jevtić, Ivana I., Savić-Vujović, Katarina, Srebro, Dragana, Vučković, Sonja M., Ivanović, Milovan, Kostić-Rajačić, Slađana, "Synthesis and pharmacological evaluation of novel cis and trans 3-substituted anilidopiperidines" in Pharmacological Reports, 72, no. 4 (2020):1069-1075,
https://doi.org/10.1007/s43440-020-00121-2 . .

TY  - DATA
AU  - Jevtić, Ivana I.
AU  - Savić-Vujović, Katarina
AU  - Srebro, Dragana
AU  - Vučković, Sonja M.
AU  - Ivanović, Milovan
AU  - Kostić-Rajačić, Slađana
PY  - 2020
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/4212
PB  - Springer
T2  - Pharmacological Reports
T1  - Supplementary data for the article: Jevtić, I. I.; Savić Vujović, K.; Srebro, D.; Vučković, S.; Ivanović, M. D.; Kostić-Rajačić, S. V. Synthesis and Pharmacological Evaluation of Novel Cis and Trans 3-Substituted Anilidopiperidines. Pharmacol. Rep 2020, 72 (4), 1069–1075. https://doi.org/10.1007/s43440-020-00121-2
UR  - https://hdl.handle.net/21.15107/rcub_cherry_4212
ER  - 

@misc{
author = "Jevtić, Ivana I. and Savić-Vujović, Katarina and Srebro, Dragana and Vučković, Sonja M. and Ivanović, Milovan and Kostić-Rajačić, Slađana",
year = "2020",
publisher = "Springer",
journal = "Pharmacological Reports",
title = "Supplementary data for the article: Jevtić, I. I.; Savić Vujović, K.; Srebro, D.; Vučković, S.; Ivanović, M. D.; Kostić-Rajačić, S. V. Synthesis and Pharmacological Evaluation of Novel Cis and Trans 3-Substituted Anilidopiperidines. Pharmacol. Rep 2020, 72 (4), 1069–1075. https://doi.org/10.1007/s43440-020-00121-2",
url = "https://hdl.handle.net/21.15107/rcub_cherry_4212"
}

Jevtić, I. I., Savić-Vujović, K., Srebro, D., Vučković, S. M., Ivanović, M.,& Kostić-Rajačić, S.. (2020). Supplementary data for the article: Jevtić, I. I.; Savić Vujović, K.; Srebro, D.; Vučković, S.; Ivanović, M. D.; Kostić-Rajačić, S. V. Synthesis and Pharmacological Evaluation of Novel Cis and Trans 3-Substituted Anilidopiperidines. Pharmacol. Rep 2020, 72 (4), 1069–1075. https://doi.org/10.1007/s43440-020-00121-2. in Pharmacological Reports
Springer..
https://hdl.handle.net/21.15107/rcub_cherry_4212

Jevtić II, Savić-Vujović K, Srebro D, Vučković SM, Ivanović M, Kostić-Rajačić S. Supplementary data for the article: Jevtić, I. I.; Savić Vujović, K.; Srebro, D.; Vučković, S.; Ivanović, M. D.; Kostić-Rajačić, S. V. Synthesis and Pharmacological Evaluation of Novel Cis and Trans 3-Substituted Anilidopiperidines. Pharmacol. Rep 2020, 72 (4), 1069–1075. https://doi.org/10.1007/s43440-020-00121-2. in Pharmacological Reports. 2020;.
https://hdl.handle.net/21.15107/rcub_cherry_4212 .

Jevtić, Ivana I., Savić-Vujović, Katarina, Srebro, Dragana, Vučković, Sonja M., Ivanović, Milovan, Kostić-Rajačić, Slađana, "Supplementary data for the article: Jevtić, I. I.; Savić Vujović, K.; Srebro, D.; Vučković, S.; Ivanović, M. D.; Kostić-Rajačić, S. V. Synthesis and Pharmacological Evaluation of Novel Cis and Trans 3-Substituted Anilidopiperidines. Pharmacol. Rep 2020, 72 (4), 1069–1075. https://doi.org/10.1007/s43440-020-00121-2" in Pharmacological Reports (2020),
https://hdl.handle.net/21.15107/rcub_cherry_4212 .

TY  - JOUR
AU  - Jevtić, Ivana I.
AU  - Penjišević, Jelena
AU  - Savić-Vujović, Katarina
AU  - Srebro, Dragana
AU  - Vučković, Sonja M.
AU  - Ivanović, Milovan
AU  - Kostić-Rajačić, Slađana
PY  - 2020
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/4243
AB  - Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for μ-opioid receptor (MOR) and dopamine D2 receptors (D2DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D2DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28–42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D2DAR using [3H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid–dopamine receptor heterobivalent ligands.
PB  - Serbian Chemical Society
T2  - Journal of the Serbian Chemical Society
T1  - μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation
VL  - 85
IS  - 6
SP  - 711
EP  - 720
DO  - 10.2298/JSC190912118J
ER  - 

@article{
author = "Jevtić, Ivana I. and Penjišević, Jelena and Savić-Vujović, Katarina and Srebro, Dragana and Vučković, Sonja M. and Ivanović, Milovan and Kostić-Rajačić, Slađana",
year = "2020",
abstract = "Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for μ-opioid receptor (MOR) and dopamine D2 receptors (D2DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D2DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28–42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D2DAR using [3H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid–dopamine receptor heterobivalent ligands.",
publisher = "Serbian Chemical Society",
journal = "Journal of the Serbian Chemical Society",
title = "μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation",
volume = "85",
number = "6",
pages = "711-720",
doi = "10.2298/JSC190912118J"
}

Jevtić, I. I., Penjišević, J., Savić-Vujović, K., Srebro, D., Vučković, S. M., Ivanović, M.,& Kostić-Rajačić, S.. (2020). μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation. in Journal of the Serbian Chemical Society
Serbian Chemical Society., 85(6), 711-720.
https://doi.org/10.2298/JSC190912118J

Jevtić II, Penjišević J, Savić-Vujović K, Srebro D, Vučković SM, Ivanović M, Kostić-Rajačić S. μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation. in Journal of the Serbian Chemical Society. 2020;85(6):711-720.
doi:10.2298/JSC190912118J .

Jevtić, Ivana I., Penjišević, Jelena, Savić-Vujović, Katarina, Srebro, Dragana, Vučković, Sonja M., Ivanović, Milovan, Kostić-Rajačić, Slađana, "μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation" in Journal of the Serbian Chemical Society, 85, no. 6 (2020):711-720,
https://doi.org/10.2298/JSC190912118J . .

TY  - JOUR
AU  - Vučković, Sonja M.
AU  - Savić-Vujović, Katarina
AU  - Srebro, Dragana
AU  - Ivanović, Milovan
AU  - Došen-Mićović, Ljiljana
AU  - Stojanović, Radan
AU  - Prostran, Milica
PY  - 2012
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/140
AB  - 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)  gt  (±)trans-3-methyl fentanyl (2) $ (±)cis-3-ethyl fentanyl (1.5)  gt  fentanyl (1) $ (±)trans-3-ethyl fentanyl (0.9)  gt  (±)cis-3-butyl fentanyl (0.064) $ (±)trans-3-butyl fentanyl (0.035)  gt  (±)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)  gt  (±)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  gt  and  lt  denotes p lt 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.
AB  - Uvod. Fentanil pripada grupi sintetskih opioidnih analgetika, 4-anilidopiperidina. Karakteriše ga visoka potentnost, brz početak i kratko trajanje dejstva. Do sada je sintetisan veliki broj analoga fentanila, kako u cilju određivanja odnosa strukture i farmakološke aktivnosti, tako i u cilju pronalaženja novog klinički korisnog analgetika. Cilj rada. U studiji su ispitivana analgetska dejstva novosintetisanih 3-alkil analoga fentanila i poređena sa fentanilom. Metod rada. Merenje analgetskog dejstva ispitivanih jedinjenja vršeno je uz pomoć testa potapanja repa pacova u toplu vodu. Rezultati. Relativna jačina jedinjenja iznosila je: (±)cis-3-metil fentanil (8)  gt  (±)trans-3-metil fentanil (2) $ (±)cis-3-etil fentanil (1,5)  gt  fentanil (1) $ (±)trans-3-etil fentanil (0,9)  gt  (±)cis-3-butil fentanil (0,064) $ (±)trans-3-butil fentanil (0,035)  gt  (±)cis-3-benzil fentanil (0,008) $ (±)trans-3-benzil fentanil (0,0055). (±)Cis-3-izopropil fentanil i (±)cis-3-fenetil fentanil nisu ispoljili dejstvo u dozama do 5 mg/kg. Dužina dejstva (ED99) iznosila je: (±)cis-3-metil fentanil (90 min)  gt  (±)trans-3-metil fentanil (40 min) # (±)cis-3-etil fentanil (60 min) $ (±)trans-3-etil fentanil (40 min) # fentanil (50 min) = (±)cis-3-butil fentanil (50 min) = (±)trans-3-butil fentanil (50 min) = (±)cis-3-benzil fentanil (50 min) = (±)trans-3-benzil fentanil (50 min). Oznake  gt  i  lt  označavaju P lt 0.05. Zaključak Zaključeno je da na analgetsku jačinu 3-alkil analoga fentanila utiče sterni faktor (voluminoznost grupe na položaju 3 piperidinskog prstena i cis/trans izomerizam). Inače, uz izuzetak 3-metil fentanila, stereohemija ne utiče značajno na dužinu dejstva 3-alkil analoga fentanila.
T2  - Engrami
T1  - 3-alkyl fentanyl analogues: Structure-activity-relationship study
T1  - 3-alkil analozi fentanila - studija odnosa strukture i aktivnost
VL  - 34
IS  - 3
SP  - 15
EP  - 26
UR  - https://hdl.handle.net/21.15107/rcub_cherry_140
ER  - 

@article{
author = "Vučković, Sonja M. and Savić-Vujović, Katarina and Srebro, Dragana and Ivanović, Milovan and Došen-Mićović, Ljiljana and Stojanović, Radan and Prostran, Milica",
year = "2012",
abstract = "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)  gt  (±)trans-3-methyl fentanyl (2) $ (±)cis-3-ethyl fentanyl (1.5)  gt  fentanyl (1) $ (±)trans-3-ethyl fentanyl (0.9)  gt  (±)cis-3-butyl fentanyl (0.064) $ (±)trans-3-butyl fentanyl (0.035)  gt  (±)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)  gt  (±)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  gt  and  lt  denotes p lt 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., Uvod. Fentanil pripada grupi sintetskih opioidnih analgetika, 4-anilidopiperidina. Karakteriše ga visoka potentnost, brz početak i kratko trajanje dejstva. Do sada je sintetisan veliki broj analoga fentanila, kako u cilju određivanja odnosa strukture i farmakološke aktivnosti, tako i u cilju pronalaženja novog klinički korisnog analgetika. Cilj rada. U studiji su ispitivana analgetska dejstva novosintetisanih 3-alkil analoga fentanila i poređena sa fentanilom. Metod rada. Merenje analgetskog dejstva ispitivanih jedinjenja vršeno je uz pomoć testa potapanja repa pacova u toplu vodu. Rezultati. Relativna jačina jedinjenja iznosila je: (±)cis-3-metil fentanil (8)  gt  (±)trans-3-metil fentanil (2) $ (±)cis-3-etil fentanil (1,5)  gt  fentanil (1) $ (±)trans-3-etil fentanil (0,9)  gt  (±)cis-3-butil fentanil (0,064) $ (±)trans-3-butil fentanil (0,035)  gt  (±)cis-3-benzil fentanil (0,008) $ (±)trans-3-benzil fentanil (0,0055). (±)Cis-3-izopropil fentanil i (±)cis-3-fenetil fentanil nisu ispoljili dejstvo u dozama do 5 mg/kg. Dužina dejstva (ED99) iznosila je: (±)cis-3-metil fentanil (90 min)  gt  (±)trans-3-metil fentanil (40 min) # (±)cis-3-etil fentanil (60 min) $ (±)trans-3-etil fentanil (40 min) # fentanil (50 min) = (±)cis-3-butil fentanil (50 min) = (±)trans-3-butil fentanil (50 min) = (±)cis-3-benzil fentanil (50 min) = (±)trans-3-benzil fentanil (50 min). Oznake  gt  i  lt  označavaju P lt 0.05. Zaključak Zaključeno je da na analgetsku jačinu 3-alkil analoga fentanila utiče sterni faktor (voluminoznost grupe na položaju 3 piperidinskog prstena i cis/trans izomerizam). Inače, uz izuzetak 3-metil fentanila, stereohemija ne utiče značajno na dužinu dejstva 3-alkil analoga fentanila.",
journal = "Engrami",
title = "3-alkyl fentanyl analogues: Structure-activity-relationship study, 3-alkil analozi fentanila - studija odnosa strukture i aktivnost",
volume = "34",
number = "3",
pages = "15-26",
url = "https://hdl.handle.net/21.15107/rcub_cherry_140"
}

Vučković, S. M., Savić-Vujović, K., Srebro, D., Ivanović, M., Došen-Mićović, L., Stojanović, R.,& Prostran, M.. (2012). 3-alkyl fentanyl analogues: Structure-activity-relationship study. in Engrami, 34(3), 15-26.
https://hdl.handle.net/21.15107/rcub_cherry_140

Vučković SM, Savić-Vujović K, Srebro D, Ivanović M, Došen-Mićović L, Stojanović R, Prostran M. 3-alkyl fentanyl analogues: Structure-activity-relationship study. in Engrami. 2012;34(3):15-26.
https://hdl.handle.net/21.15107/rcub_cherry_140 .

Vučković, Sonja M., Savić-Vujović, Katarina, Srebro, Dragana, Ivanović, Milovan, Došen-Mićović, Ljiljana, Stojanović, Radan, Prostran, Milica, "3-alkyl fentanyl analogues: Structure-activity-relationship study" in Engrami, 34, no. 3 (2012):15-26,
https://hdl.handle.net/21.15107/rcub_cherry_140 .