TY  - JOUR
AU  - Jevtić, Ivana I.
AU  - Došen-Mićović, Ljiljana
AU  - Ivanović, Evica R.
AU  - Todorović, Nina
AU  - Ivanović, Milovan
PY  - 2017
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2492
AB  - The synthesis of orthogonally protected cis- and trans-3-amino-4-anilidopiperidine derivatives has been accomplished in six steps, starting from readily accessible 4-piperidone derivatives. The last three steps, i.e., N-acylation, Hofmann rearrangement, and carbamate cleavage, involved separated (+/-)-cis and (+/-)-trans intermediates. Complete retention of configuration was observed at position 3 of the piperidine ring. Specifically protected positions 1 and 3 at the piperidine scaffold allow for selective deprotection and introduction of diverse substituents at the respective nitrogen sites. The orthogonally protected anilidopiperidines open avenues to potentially pharmacologically active compounds, including opioids and various bivalent ligands for G protein-coupled receptors. In addition, a prototype of a novel class of fentanyl derivatives, possessing a 3-amino group, was synthesized by using the same approach.
PB  - Georg Thieme Verlag Kg, Stuttgart
T2  - Synthesis, Stuttgart
T1  - Synthesis of Orthogonally Protected (+/-)-3-Amino-4-anilidopiperidines and (+/-)-3-N-Carbomethoxyfentanyl
VL  - 49
IS  - 14
SP  - 3126
EP  - 3136
DO  - 10.1055/s-0036-1588985
ER  - 

@article{
author = "Jevtić, Ivana I. and Došen-Mićović, Ljiljana and Ivanović, Evica R. and Todorović, Nina and Ivanović, Milovan",
year = "2017",
abstract = "The synthesis of orthogonally protected cis- and trans-3-amino-4-anilidopiperidine derivatives has been accomplished in six steps, starting from readily accessible 4-piperidone derivatives. The last three steps, i.e., N-acylation, Hofmann rearrangement, and carbamate cleavage, involved separated (+/-)-cis and (+/-)-trans intermediates. Complete retention of configuration was observed at position 3 of the piperidine ring. Specifically protected positions 1 and 3 at the piperidine scaffold allow for selective deprotection and introduction of diverse substituents at the respective nitrogen sites. The orthogonally protected anilidopiperidines open avenues to potentially pharmacologically active compounds, including opioids and various bivalent ligands for G protein-coupled receptors. In addition, a prototype of a novel class of fentanyl derivatives, possessing a 3-amino group, was synthesized by using the same approach.",
publisher = "Georg Thieme Verlag Kg, Stuttgart",
journal = "Synthesis, Stuttgart",
title = "Synthesis of Orthogonally Protected (+/-)-3-Amino-4-anilidopiperidines and (+/-)-3-N-Carbomethoxyfentanyl",
volume = "49",
number = "14",
pages = "3126-3136",
doi = "10.1055/s-0036-1588985"
}

Jevtić, I. I., Došen-Mićović, L., Ivanović, E. R., Todorović, N.,& Ivanović, M.. (2017). Synthesis of Orthogonally Protected (+/-)-3-Amino-4-anilidopiperidines and (+/-)-3-N-Carbomethoxyfentanyl. in Synthesis, Stuttgart
Georg Thieme Verlag Kg, Stuttgart., 49(14), 3126-3136.
https://doi.org/10.1055/s-0036-1588985

Jevtić II, Došen-Mićović L, Ivanović ER, Todorović N, Ivanović M. Synthesis of Orthogonally Protected (+/-)-3-Amino-4-anilidopiperidines and (+/-)-3-N-Carbomethoxyfentanyl. in Synthesis, Stuttgart. 2017;49(14):3126-3136.
doi:10.1055/s-0036-1588985 .

Jevtić, Ivana I., Došen-Mićović, Ljiljana, Ivanović, Evica R., Todorović, Nina, Ivanović, Milovan, "Synthesis of Orthogonally Protected (+/-)-3-Amino-4-anilidopiperidines and (+/-)-3-N-Carbomethoxyfentanyl" in Synthesis, Stuttgart, 49, no. 14 (2017):3126-3136,
https://doi.org/10.1055/s-0036-1588985 . .

TY  - JOUR
AU  - Jevtić, Ivana I.
AU  - Došen-Mićović, Ljiljana
AU  - Ivanović, Evica R.
AU  - Todorović, Nina
AU  - Ivanović, Milovan
PY  - 2017
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/3248
AB  - The synthesis of orthogonally protected cis- and trans-3-amino-4-anilidopiperidine derivatives has been accomplished in six steps, starting from readily accessible 4-piperidone derivatives. The last three steps, i.e., N-acylation, Hofmann rearrangement, and carbamate cleavage, involved separated (+/-)-cis and (+/-)-trans intermediates. Complete retention of configuration was observed at position 3 of the piperidine ring. Specifically protected positions 1 and 3 at the piperidine scaffold allow for selective deprotection and introduction of diverse substituents at the respective nitrogen sites. The orthogonally protected anilidopiperidines open avenues to potentially pharmacologically active compounds, including opioids and various bivalent ligands for G protein-coupled receptors. In addition, a prototype of a novel class of fentanyl derivatives, possessing a 3-amino group, was synthesized by using the same approach.
PB  - Georg Thieme Verlag Kg, Stuttgart
T2  - Synthesis
T1  - Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl
VL  - 49
IS  - 14
SP  - 3126
EP  - 3136
DO  - 10.1055/s-0036-1588985
ER  - 

@article{
author = "Jevtić, Ivana I. and Došen-Mićović, Ljiljana and Ivanović, Evica R. and Todorović, Nina and Ivanović, Milovan",
year = "2017",
abstract = "The synthesis of orthogonally protected cis- and trans-3-amino-4-anilidopiperidine derivatives has been accomplished in six steps, starting from readily accessible 4-piperidone derivatives. The last three steps, i.e., N-acylation, Hofmann rearrangement, and carbamate cleavage, involved separated (+/-)-cis and (+/-)-trans intermediates. Complete retention of configuration was observed at position 3 of the piperidine ring. Specifically protected positions 1 and 3 at the piperidine scaffold allow for selective deprotection and introduction of diverse substituents at the respective nitrogen sites. The orthogonally protected anilidopiperidines open avenues to potentially pharmacologically active compounds, including opioids and various bivalent ligands for G protein-coupled receptors. In addition, a prototype of a novel class of fentanyl derivatives, possessing a 3-amino group, was synthesized by using the same approach.",
publisher = "Georg Thieme Verlag Kg, Stuttgart",
journal = "Synthesis",
title = "Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl",
volume = "49",
number = "14",
pages = "3126-3136",
doi = "10.1055/s-0036-1588985"
}

Jevtić, I. I., Došen-Mićović, L., Ivanović, E. R., Todorović, N.,& Ivanović, M.. (2017). Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl. in Synthesis
Georg Thieme Verlag Kg, Stuttgart., 49(14), 3126-3136.
https://doi.org/10.1055/s-0036-1588985

Jevtić II, Došen-Mićović L, Ivanović ER, Todorović N, Ivanović M. Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl. in Synthesis. 2017;49(14):3126-3136.
doi:10.1055/s-0036-1588985 .

Jevtić, Ivana I., Došen-Mićović, Ljiljana, Ivanović, Evica R., Todorović, Nina, Ivanović, Milovan, "Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl" in Synthesis, 49, no. 14 (2017):3126-3136,
https://doi.org/10.1055/s-0036-1588985 . .

TY  - DATA
AU  - Jevtić, Ivana I.
AU  - Došen-Mićović, Ljiljana
AU  - Ivanović, Evica R.
AU  - Todorović, Nina
AU  - Ivanović, Milovan
PY  - 2017
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/3249
PB  - Georg Thieme Verlag Kg, Stuttgart
T2  - Synthesis
T1  - Supplementary material for the article: Jevtić, I. I.; Došen-Mićović, L. I.; Ivanović, E. R.; Todorović, N. M.; Ivanović, M. D. Synthesis of Orthogonally Protected (±)-3-Amino-4-Anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl. Synthesis (Germany) 2017, 49 (14), 3126–3136. https://doi.org/10.1055/s-0036-1588985
UR  - https://hdl.handle.net/21.15107/rcub_cherry_3249
ER  - 

@misc{
author = "Jevtić, Ivana I. and Došen-Mićović, Ljiljana and Ivanović, Evica R. and Todorović, Nina and Ivanović, Milovan",
year = "2017",
publisher = "Georg Thieme Verlag Kg, Stuttgart",
journal = "Synthesis",
title = "Supplementary material for the article: Jevtić, I. I.; Došen-Mićović, L. I.; Ivanović, E. R.; Todorović, N. M.; Ivanović, M. D. Synthesis of Orthogonally Protected (±)-3-Amino-4-Anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl. Synthesis (Germany) 2017, 49 (14), 3126–3136. https://doi.org/10.1055/s-0036-1588985",
url = "https://hdl.handle.net/21.15107/rcub_cherry_3249"
}

Jevtić, I. I., Došen-Mićović, L., Ivanović, E. R., Todorović, N.,& Ivanović, M.. (2017). Supplementary material for the article: Jevtić, I. I.; Došen-Mićović, L. I.; Ivanović, E. R.; Todorović, N. M.; Ivanović, M. D. Synthesis of Orthogonally Protected (±)-3-Amino-4-Anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl. Synthesis (Germany) 2017, 49 (14), 3126–3136. https://doi.org/10.1055/s-0036-1588985. in Synthesis
Georg Thieme Verlag Kg, Stuttgart..
https://hdl.handle.net/21.15107/rcub_cherry_3249

Jevtić II, Došen-Mićović L, Ivanović ER, Todorović N, Ivanović M. Supplementary material for the article: Jevtić, I. I.; Došen-Mićović, L. I.; Ivanović, E. R.; Todorović, N. M.; Ivanović, M. D. Synthesis of Orthogonally Protected (±)-3-Amino-4-Anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl. Synthesis (Germany) 2017, 49 (14), 3126–3136. https://doi.org/10.1055/s-0036-1588985. in Synthesis. 2017;.
https://hdl.handle.net/21.15107/rcub_cherry_3249 .

Jevtić, Ivana I., Došen-Mićović, Ljiljana, Ivanović, Evica R., Todorović, Nina, Ivanović, Milovan, "Supplementary material for the article: Jevtić, I. I.; Došen-Mićović, L. I.; Ivanović, E. R.; Todorović, N. M.; Ivanović, M. D. Synthesis of Orthogonally Protected (±)-3-Amino-4-Anilidopiperidines and (±)-3- N -Carbomethoxyfentanyl. Synthesis (Germany) 2017, 49 (14), 3126–3136. https://doi.org/10.1055/s-0036-1588985" in Synthesis (2017),
https://hdl.handle.net/21.15107/rcub_cherry_3249 .

TY  - JOUR
AU  - Popović-Djordjević, Jelena
AU  - Stepanović, Stepan
AU  - Došen-Mićović, Ljiljana
AU  - Ivanović, Evica R.
AU  - Ivanović, Milovan
PY  - 2016
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/115
AB  - It was found that NaH suspension in DMSO was highly activated when reacted with an alcohol. The in situ generated NaH/alkoxide mixture permitted very rapid and complete deprotonation and acylation of various cyclic ketones with alkyl carbonates at ambient temperature. Activated NaH/alkoxide in DMSO is particularly effective in Dieckmann condensations, where it affords 5- and 6-membered carbocyclic or N-containing heterocyclic β-keto esters in high yields. A heterocyclic Dieckmann condensation was performed on a molar scale, demonstrating the scalability of the procedure. Besides, DMSO is non-toxic, relatively inexpensive and environmentally benign solvent. © 2016 The Author(s). Published by Taylor & Francis.
T2  - Green Chemistry Letters and Reviews
T1  - High-yielding method for preparation of carbocyclic or N-containing heterocyclic β-keto esters using in situ activated sodium hydride in dimethyl sulphoxide
VL  - 9
IS  - 1
SP  - 61
EP  - 68
DO  - 10.1080/17518253.2016.1145744
ER  - 

@article{
author = "Popović-Djordjević, Jelena and Stepanović, Stepan and Došen-Mićović, Ljiljana and Ivanović, Evica R. and Ivanović, Milovan",
year = "2016",
abstract = "It was found that NaH suspension in DMSO was highly activated when reacted with an alcohol. The in situ generated NaH/alkoxide mixture permitted very rapid and complete deprotonation and acylation of various cyclic ketones with alkyl carbonates at ambient temperature. Activated NaH/alkoxide in DMSO is particularly effective in Dieckmann condensations, where it affords 5- and 6-membered carbocyclic or N-containing heterocyclic β-keto esters in high yields. A heterocyclic Dieckmann condensation was performed on a molar scale, demonstrating the scalability of the procedure. Besides, DMSO is non-toxic, relatively inexpensive and environmentally benign solvent. © 2016 The Author(s). Published by Taylor & Francis.",
journal = "Green Chemistry Letters and Reviews",
title = "High-yielding method for preparation of carbocyclic or N-containing heterocyclic β-keto esters using in situ activated sodium hydride in dimethyl sulphoxide",
volume = "9",
number = "1",
pages = "61-68",
doi = "10.1080/17518253.2016.1145744"
}

Popović-Djordjević, J., Stepanović, S., Došen-Mićović, L., Ivanović, E. R.,& Ivanović, M.. (2016). High-yielding method for preparation of carbocyclic or N-containing heterocyclic β-keto esters using in situ activated sodium hydride in dimethyl sulphoxide. in Green Chemistry Letters and Reviews, 9(1), 61-68.
https://doi.org/10.1080/17518253.2016.1145744

Popović-Djordjević J, Stepanović S, Došen-Mićović L, Ivanović ER, Ivanović M. High-yielding method for preparation of carbocyclic or N-containing heterocyclic β-keto esters using in situ activated sodium hydride in dimethyl sulphoxide. in Green Chemistry Letters and Reviews. 2016;9(1):61-68.
doi:10.1080/17518253.2016.1145744 .

Popović-Djordjević, Jelena, Stepanović, Stepan, Došen-Mićović, Ljiljana, Ivanović, Evica R., Ivanović, Milovan, "High-yielding method for preparation of carbocyclic or N-containing heterocyclic β-keto esters using in situ activated sodium hydride in dimethyl sulphoxide" in Green Chemistry Letters and Reviews, 9, no. 1 (2016):61-68,
https://doi.org/10.1080/17518253.2016.1145744 . .

TY  - JOUR
AU  - Popović-Djordjević, Jelena
AU  - Stepanović, Stepan
AU  - Došen-Mićović, Ljiljana
AU  - Ivanović, Evica R.
AU  - Ivanović, Milovan
PY  - 2016
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/3522
T2  - Green Chemistry Letters and Reviews
T1  - Supplementary data for the article: Popović-Djordjević, J.; Stepanović, S.; Došen-Mićović, L.; Ivanović, E.; Ivanović, M. D. High-Yielding Method for Preparation of Carbocyclic or N-Containing Heterocyclic β-Keto Esters Using in Situ Activated Sodium Hydride in Dimethyl Sulphoxide. Green Chemistry Letters and Reviews 2016, 9 (1), 61–68. https://doi.org/10.1080/17518253.2016.1145744
UR  - https://hdl.handle.net/21.15107/rcub_cherry_3522
ER  - 

@article{
author = "Popović-Djordjević, Jelena and Stepanović, Stepan and Došen-Mićović, Ljiljana and Ivanović, Evica R. and Ivanović, Milovan",
year = "2016",
journal = "Green Chemistry Letters and Reviews",
title = "Supplementary data for the article: Popović-Djordjević, J.; Stepanović, S.; Došen-Mićović, L.; Ivanović, E.; Ivanović, M. D. High-Yielding Method for Preparation of Carbocyclic or N-Containing Heterocyclic β-Keto Esters Using in Situ Activated Sodium Hydride in Dimethyl Sulphoxide. Green Chemistry Letters and Reviews 2016, 9 (1), 61–68. https://doi.org/10.1080/17518253.2016.1145744",
url = "https://hdl.handle.net/21.15107/rcub_cherry_3522"
}

Popović-Djordjević, J., Stepanović, S., Došen-Mićović, L., Ivanović, E. R.,& Ivanović, M.. (2016). Supplementary data for the article: Popović-Djordjević, J.; Stepanović, S.; Došen-Mićović, L.; Ivanović, E.; Ivanović, M. D. High-Yielding Method for Preparation of Carbocyclic or N-Containing Heterocyclic β-Keto Esters Using in Situ Activated Sodium Hydride in Dimethyl Sulphoxide. Green Chemistry Letters and Reviews 2016, 9 (1), 61–68. https://doi.org/10.1080/17518253.2016.1145744. in Green Chemistry Letters and Reviews.
https://hdl.handle.net/21.15107/rcub_cherry_3522

Popović-Djordjević J, Stepanović S, Došen-Mićović L, Ivanović ER, Ivanović M. Supplementary data for the article: Popović-Djordjević, J.; Stepanović, S.; Došen-Mićović, L.; Ivanović, E.; Ivanović, M. D. High-Yielding Method for Preparation of Carbocyclic or N-Containing Heterocyclic β-Keto Esters Using in Situ Activated Sodium Hydride in Dimethyl Sulphoxide. Green Chemistry Letters and Reviews 2016, 9 (1), 61–68. https://doi.org/10.1080/17518253.2016.1145744. in Green Chemistry Letters and Reviews. 2016;.
https://hdl.handle.net/21.15107/rcub_cherry_3522 .

Popović-Djordjević, Jelena, Stepanović, Stepan, Došen-Mićović, Ljiljana, Ivanović, Evica R., Ivanović, Milovan, "Supplementary data for the article: Popović-Djordjević, J.; Stepanović, S.; Došen-Mićović, L.; Ivanović, E.; Ivanović, M. D. High-Yielding Method for Preparation of Carbocyclic or N-Containing Heterocyclic β-Keto Esters Using in Situ Activated Sodium Hydride in Dimethyl Sulphoxide. Green Chemistry Letters and Reviews 2016, 9 (1), 61–68. https://doi.org/10.1080/17518253.2016.1145744" in Green Chemistry Letters and Reviews (2016),
https://hdl.handle.net/21.15107/rcub_cherry_3522 .

TY  - JOUR
AU  - Jevtić, Ivana I.
AU  - Došen-Mićović, Ljiljana
AU  - Ivanović, Evica R.
AU  - Ivanović, Milovan
PY  - 2016
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/1935
AB  - An efficient, one-pot procedure for the Hofmann rearrangement of aromatic and aliphatic amides has been developed. Methyl and benzyl carbamates are produced with N-bromoacetamide in the presence of lithium hydroxide or lithium methoxide, in high yields. -Phenylamino amides gave five-membered cyclic ureas stereospecifically. Side products of aryl or benzyl bromination were minimized. This procedure offers an easy access to various protected amines or diamines, which represent important synthetic precursors.
PB  - Georg Thieme Verlag Kg, Stuttgart
T2  - Synthesis, Stuttgart
T1  - Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide
VL  - 48
IS  - 10
SP  - 1550
EP  - 1560
DO  - 10.1055/s-0035-1561405
ER  - 

@article{
author = "Jevtić, Ivana I. and Došen-Mićović, Ljiljana and Ivanović, Evica R. and Ivanović, Milovan",
year = "2016",
abstract = "An efficient, one-pot procedure for the Hofmann rearrangement of aromatic and aliphatic amides has been developed. Methyl and benzyl carbamates are produced with N-bromoacetamide in the presence of lithium hydroxide or lithium methoxide, in high yields. -Phenylamino amides gave five-membered cyclic ureas stereospecifically. Side products of aryl or benzyl bromination were minimized. This procedure offers an easy access to various protected amines or diamines, which represent important synthetic precursors.",
publisher = "Georg Thieme Verlag Kg, Stuttgart",
journal = "Synthesis, Stuttgart",
title = "Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide",
volume = "48",
number = "10",
pages = "1550-1560",
doi = "10.1055/s-0035-1561405"
}

Jevtić, I. I., Došen-Mićović, L., Ivanović, E. R.,& Ivanović, M.. (2016). Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide. in Synthesis, Stuttgart
Georg Thieme Verlag Kg, Stuttgart., 48(10), 1550-1560.
https://doi.org/10.1055/s-0035-1561405

Jevtić II, Došen-Mićović L, Ivanović ER, Ivanović M. Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide. in Synthesis, Stuttgart. 2016;48(10):1550-1560.
doi:10.1055/s-0035-1561405 .

Jevtić, Ivana I., Došen-Mićović, Ljiljana, Ivanović, Evica R., Ivanović, Milovan, "Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide" in Synthesis, Stuttgart, 48, no. 10 (2016):1550-1560,
https://doi.org/10.1055/s-0035-1561405 . .

TY  - DATA
AU  - Jevtić, Ivana I.
AU  - Došen-Mićović, Ljiljana
AU  - Ivanović, Evica R.
AU  - Ivanović, Milovan
PY  - 2016
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/3523
PB  - Georg Thieme Verlag Kg, Stuttgart
T2  - Synthesis, Stuttgart
T1  - Supplementary data for the article: Jevtić, I. I.; Došen-Mićović, L.; Ivanović, E. R.; Ivanović, M. D. Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide. Synthesis (Germany) 2016, 48 (10), 1550–1560. https://doi.org/10.1055/s-0035-1561405
UR  - https://hdl.handle.net/21.15107/rcub_cherry_3523
ER  - 

@misc{
author = "Jevtić, Ivana I. and Došen-Mićović, Ljiljana and Ivanović, Evica R. and Ivanović, Milovan",
year = "2016",
publisher = "Georg Thieme Verlag Kg, Stuttgart",
journal = "Synthesis, Stuttgart",
title = "Supplementary data for the article: Jevtić, I. I.; Došen-Mićović, L.; Ivanović, E. R.; Ivanović, M. D. Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide. Synthesis (Germany) 2016, 48 (10), 1550–1560. https://doi.org/10.1055/s-0035-1561405",
url = "https://hdl.handle.net/21.15107/rcub_cherry_3523"
}

Jevtić, I. I., Došen-Mićović, L., Ivanović, E. R.,& Ivanović, M.. (2016). Supplementary data for the article: Jevtić, I. I.; Došen-Mićović, L.; Ivanović, E. R.; Ivanović, M. D. Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide. Synthesis (Germany) 2016, 48 (10), 1550–1560. https://doi.org/10.1055/s-0035-1561405. in Synthesis, Stuttgart
Georg Thieme Verlag Kg, Stuttgart..
https://hdl.handle.net/21.15107/rcub_cherry_3523

Jevtić II, Došen-Mićović L, Ivanović ER, Ivanović M. Supplementary data for the article: Jevtić, I. I.; Došen-Mićović, L.; Ivanović, E. R.; Ivanović, M. D. Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide. Synthesis (Germany) 2016, 48 (10), 1550–1560. https://doi.org/10.1055/s-0035-1561405. in Synthesis, Stuttgart. 2016;.
https://hdl.handle.net/21.15107/rcub_cherry_3523 .

Jevtić, Ivana I., Došen-Mićović, Ljiljana, Ivanović, Evica R., Ivanović, Milovan, "Supplementary data for the article: Jevtić, I. I.; Došen-Mićović, L.; Ivanović, E. R.; Ivanović, M. D. Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide. Synthesis (Germany) 2016, 48 (10), 1550–1560. https://doi.org/10.1055/s-0035-1561405" in Synthesis, Stuttgart (2016),
https://hdl.handle.net/21.15107/rcub_cherry_3523 .

TY  - JOUR
AU  - Senćanski, Milan
AU  - Ivanović, Milovan
AU  - Došen-Mićović, Ljiljana
PY  - 2014
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/1801
AB  - An opioid receptor like (ORL1) receptor is one of a family of G-protein-coupled receptors (GPCR); it represents a new pharmaceutical target with extensive therapeutic potential for the regulation of important biological functions such as nociception, mood disorders, drug abuse, learning or cardiovascular control. Although the crystal structure of the inactive form of the ORL1 receptor has been determined, little is known about its activation. By using X-ray structures of the beta 2-adrenegic receptor in its inactive (2RH1) and active (3P0G) states as templates, inactive and active homology models of the ORL1 receptor were constructed. Structurally diverse sets of strongly binding antagonists and agonists were docked with both ORL1 receptor forms. The major receptor-ligand interactions responsible for antagonist and agonist binding were identified. Although both sets of ligands, agonists and antagonists, bind to the same region of the receptor, they occupy partially different binding pockets. Agonists bind to the inactive receptor in a slightly different manner than antagonists. This difference is more pronounced in binding to the active ORL1 receptor model and points to the amino acids at the extracellular end of TM6, suggesting that this region is important for receptor-activation. (C) 2014 Institute of Chemistry, Slovak Academy of Sciences
PB  - Springer International Publishing Ag, Cham
T2  - CHEMICAL PAPERS
T1  - Modelling of ORL1 receptor-ligand interactions
VL  - 68
IS  - 10
SP  - 1305
EP  - 1316
DO  - 10.2478/s11696-014-0577-z
ER  - 

@article{
author = "Senćanski, Milan and Ivanović, Milovan and Došen-Mićović, Ljiljana",
year = "2014",
abstract = "An opioid receptor like (ORL1) receptor is one of a family of G-protein-coupled receptors (GPCR); it represents a new pharmaceutical target with extensive therapeutic potential for the regulation of important biological functions such as nociception, mood disorders, drug abuse, learning or cardiovascular control. Although the crystal structure of the inactive form of the ORL1 receptor has been determined, little is known about its activation. By using X-ray structures of the beta 2-adrenegic receptor in its inactive (2RH1) and active (3P0G) states as templates, inactive and active homology models of the ORL1 receptor were constructed. Structurally diverse sets of strongly binding antagonists and agonists were docked with both ORL1 receptor forms. The major receptor-ligand interactions responsible for antagonist and agonist binding were identified. Although both sets of ligands, agonists and antagonists, bind to the same region of the receptor, they occupy partially different binding pockets. Agonists bind to the inactive receptor in a slightly different manner than antagonists. This difference is more pronounced in binding to the active ORL1 receptor model and points to the amino acids at the extracellular end of TM6, suggesting that this region is important for receptor-activation. (C) 2014 Institute of Chemistry, Slovak Academy of Sciences",
publisher = "Springer International Publishing Ag, Cham",
journal = "CHEMICAL PAPERS",
title = "Modelling of ORL1 receptor-ligand interactions",
volume = "68",
number = "10",
pages = "1305-1316",
doi = "10.2478/s11696-014-0577-z"
}

Senćanski, M., Ivanović, M.,& Došen-Mićović, L.. (2014). Modelling of ORL1 receptor-ligand interactions. in CHEMICAL PAPERS
Springer International Publishing Ag, Cham., 68(10), 1305-1316.
https://doi.org/10.2478/s11696-014-0577-z

Senćanski M, Ivanović M, Došen-Mićović L. Modelling of ORL1 receptor-ligand interactions. in CHEMICAL PAPERS. 2014;68(10):1305-1316.
doi:10.2478/s11696-014-0577-z .

Senćanski, Milan, Ivanović, Milovan, Došen-Mićović, Ljiljana, "Modelling of ORL1 receptor-ligand interactions" in CHEMICAL PAPERS, 68, no. 10 (2014):1305-1316,
https://doi.org/10.2478/s11696-014-0577-z . .

TY  - JOUR
AU  - Vujovic, Katarina R. Savic
AU  - Vuckovic, Sonja
AU  - Srebro, Dragana
AU  - Ivanović, Milovan
AU  - Došen-Mićović, Ljiljana
AU  - Vucetic, Cedomir
AU  - Dzoljic, Eleonora
AU  - Prostran, Milica
PY  - 2013
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/1633
AB  - In addition to producing antinociception, opioids exert profound effects on body temperature. This study aimed at comparing antinociceptive and hyperthermic responses between two groups of mu-opioid receptor agonists: fentanyl (4-anilinopiperidine-type) and morphine (phenanthrene-type) derivatives in rats. Analgesic activity was assessed by tail immersion test and the body temperature by insertion of a thermometer probe into the colon. Fentanyl (F), (+/-)-cis-3-methyl fentanyl (CM), (+/-)-cis-3-carbomethoxy fentanyl (C), (+/-)trans-3-carbomethoxy fentanyl (T) and (+/-)-cis-3 butyl fentanyl (B) produced dose-dependent increase in antinociception and hyperthermia. The relative order of analgesic potency was: CM(11.27) gt  F(1) gt  C(0.35)a parts per thousand yenT(0.11)a parts per thousand yenB(0.056). Similar to this, the relative order of hyperthermic potency was: CM(8.43) gt  F(1) gt  C(0.46)a parts per thousand yenT(0.11)a parts per thousand yenB(0.076). Morphine (M), oxycodone (O), thebacon (T) and 6,14-ethenomorphinan-7-methanol, 4,5-epoxy-6-fluoro-3-hydroxy-alpha,alpha,17-trimethyl-, (5 alpha,7 alpha) (E) also produced dose-dependent increase in antinociception and hyperthermia. Among morphine derivatives the relative order of analgesic potency was: E(56) gt  O(5)a parts per thousand yenT(2.6) gt  M(1), and similar to this, the relative order of hyperthermic potency was: E(37) gt  O(3)a parts per thousand yenT(2.3) gt  M(1). Morphine (phenanthrene-type) and fentanyl (4-anilinopiperidine-type) derivatives produced hyperthermia in rats at doses about 2 times lower, and 6-11 times higher, than their median antinociceptive doses, respectively. This study is first to identify difference between these two classes of opioid drugs in their potencies in producing hyperthermia. Further studies are needed to clarify the significance of these findings.
PB  - Pharmaceutical Soc Korea, Seoul
T2  - Archives of Pharmacal Research
T1  - A comparison of the antinociceptive and temperature responses to morphine and fentanyl derivatives in rats
VL  - 36
IS  - 4
SP  - 501
EP  - 508
DO  - 10.1007/s12272-013-0072-z
ER  - 

@article{
author = "Vujovic, Katarina R. Savic and Vuckovic, Sonja and Srebro, Dragana and Ivanović, Milovan and Došen-Mićović, Ljiljana and Vucetic, Cedomir and Dzoljic, Eleonora and Prostran, Milica",
year = "2013",
abstract = "In addition to producing antinociception, opioids exert profound effects on body temperature. This study aimed at comparing antinociceptive and hyperthermic responses between two groups of mu-opioid receptor agonists: fentanyl (4-anilinopiperidine-type) and morphine (phenanthrene-type) derivatives in rats. Analgesic activity was assessed by tail immersion test and the body temperature by insertion of a thermometer probe into the colon. Fentanyl (F), (+/-)-cis-3-methyl fentanyl (CM), (+/-)-cis-3-carbomethoxy fentanyl (C), (+/-)trans-3-carbomethoxy fentanyl (T) and (+/-)-cis-3 butyl fentanyl (B) produced dose-dependent increase in antinociception and hyperthermia. The relative order of analgesic potency was: CM(11.27) gt  F(1) gt  C(0.35)a parts per thousand yenT(0.11)a parts per thousand yenB(0.056). Similar to this, the relative order of hyperthermic potency was: CM(8.43) gt  F(1) gt  C(0.46)a parts per thousand yenT(0.11)a parts per thousand yenB(0.076). Morphine (M), oxycodone (O), thebacon (T) and 6,14-ethenomorphinan-7-methanol, 4,5-epoxy-6-fluoro-3-hydroxy-alpha,alpha,17-trimethyl-, (5 alpha,7 alpha) (E) also produced dose-dependent increase in antinociception and hyperthermia. Among morphine derivatives the relative order of analgesic potency was: E(56) gt  O(5)a parts per thousand yenT(2.6) gt  M(1), and similar to this, the relative order of hyperthermic potency was: E(37) gt  O(3)a parts per thousand yenT(2.3) gt  M(1). Morphine (phenanthrene-type) and fentanyl (4-anilinopiperidine-type) derivatives produced hyperthermia in rats at doses about 2 times lower, and 6-11 times higher, than their median antinociceptive doses, respectively. This study is first to identify difference between these two classes of opioid drugs in their potencies in producing hyperthermia. Further studies are needed to clarify the significance of these findings.",
publisher = "Pharmaceutical Soc Korea, Seoul",
journal = "Archives of Pharmacal Research",
title = "A comparison of the antinociceptive and temperature responses to morphine and fentanyl derivatives in rats",
volume = "36",
number = "4",
pages = "501-508",
doi = "10.1007/s12272-013-0072-z"
}

Vujovic, K. R. S., Vuckovic, S., Srebro, D., Ivanović, M., Došen-Mićović, L., Vucetic, C., Dzoljic, E.,& Prostran, M.. (2013). A comparison of the antinociceptive and temperature responses to morphine and fentanyl derivatives in rats. in Archives of Pharmacal Research
Pharmaceutical Soc Korea, Seoul., 36(4), 501-508.
https://doi.org/10.1007/s12272-013-0072-z

Vujovic KRS, Vuckovic S, Srebro D, Ivanović M, Došen-Mićović L, Vucetic C, Dzoljic E, Prostran M. A comparison of the antinociceptive and temperature responses to morphine and fentanyl derivatives in rats. in Archives of Pharmacal Research. 2013;36(4):501-508.
doi:10.1007/s12272-013-0072-z .

Vujovic, Katarina R. Savic, Vuckovic, Sonja, Srebro, Dragana, Ivanović, Milovan, Došen-Mićović, Ljiljana, Vucetic, Cedomir, Dzoljic, Eleonora, Prostran, Milica, "A comparison of the antinociceptive and temperature responses to morphine and fentanyl derivatives in rats" in Archives of Pharmacal Research, 36, no. 4 (2013):501-508,
https://doi.org/10.1007/s12272-013-0072-z . .

TY  - JOUR
AU  - Senćanski, Milan
AU  - Šukalović, Vladimir
AU  - Došen-Mićović, Ljiljana
AU  - Šoškić, Vukić
AU  - Andrić, Deana
AU  - Roglić, Goran
AU  - Kostić-Rajačić, Slađana
PY  - 2012
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/1567
AB  - Molecular modelling studies were undertaken in order to identify key interactions of selected ligands with alpha(1A) adrenergic receptor, responsible for their binding and presumably receptor activation. The previously made model of alpha(1A) adrenergic receptor was optimized by molecular dynamics and different arylpiperazine ligands were docked. The results show a high correlation to the experimentally determined binding affinities. Ligand orientations and its interactions with specific amino acid residues in the binding site explain trends in its structure-activity relationship. The key interactions for those trends are mainly aromatic, which are suggested by the calculation of their ESP surfaces.
PB  - Inst Materials Physics, Bucharest
T2  - Digest Journal of Nanomaterials and Biostructures
T1  - Modeling Interactions of Alpha(1a) Adrenergic Receptor and Different Arylpiperazine Ligands
VL  - 7
IS  - 4
SP  - 1767
EP  - 1777
UR  - https://hdl.handle.net/21.15107/rcub_cherry_1567
ER  - 

@article{
author = "Senćanski, Milan and Šukalović, Vladimir and Došen-Mićović, Ljiljana and Šoškić, Vukić and Andrić, Deana and Roglić, Goran and Kostić-Rajačić, Slađana",
year = "2012",
abstract = "Molecular modelling studies were undertaken in order to identify key interactions of selected ligands with alpha(1A) adrenergic receptor, responsible for their binding and presumably receptor activation. The previously made model of alpha(1A) adrenergic receptor was optimized by molecular dynamics and different arylpiperazine ligands were docked. The results show a high correlation to the experimentally determined binding affinities. Ligand orientations and its interactions with specific amino acid residues in the binding site explain trends in its structure-activity relationship. The key interactions for those trends are mainly aromatic, which are suggested by the calculation of their ESP surfaces.",
publisher = "Inst Materials Physics, Bucharest",
journal = "Digest Journal of Nanomaterials and Biostructures",
title = "Modeling Interactions of Alpha(1a) Adrenergic Receptor and Different Arylpiperazine Ligands",
volume = "7",
number = "4",
pages = "1767-1777",
url = "https://hdl.handle.net/21.15107/rcub_cherry_1567"
}

Senćanski, M., Šukalović, V., Došen-Mićović, L., Šoškić, V., Andrić, D., Roglić, G.,& Kostić-Rajačić, S.. (2012). Modeling Interactions of Alpha(1a) Adrenergic Receptor and Different Arylpiperazine Ligands. in Digest Journal of Nanomaterials and Biostructures
Inst Materials Physics, Bucharest., 7(4), 1767-1777.
https://hdl.handle.net/21.15107/rcub_cherry_1567

Senćanski M, Šukalović V, Došen-Mićović L, Šoškić V, Andrić D, Roglić G, Kostić-Rajačić S. Modeling Interactions of Alpha(1a) Adrenergic Receptor and Different Arylpiperazine Ligands. in Digest Journal of Nanomaterials and Biostructures. 2012;7(4):1767-1777.
https://hdl.handle.net/21.15107/rcub_cherry_1567 .

Senćanski, Milan, Šukalović, Vladimir, Došen-Mićović, Ljiljana, Šoškić, Vukić, Andrić, Deana, Roglić, Goran, Kostić-Rajačić, Slađana, "Modeling Interactions of Alpha(1a) Adrenergic Receptor and Different Arylpiperazine Ligands" in Digest Journal of Nanomaterials and Biostructures, 7, no. 4 (2012):1767-1777,
https://hdl.handle.net/21.15107/rcub_cherry_1567 .

TY  - JOUR
AU  - Sencanski, M.V.
AU  - Šukalović, Vladimir
AU  - Došen-Mićović, Ljiljana
AU  - Šoškić, Vukić
AU  - Andrić, Deana
AU  - Roglić, Goran
AU  - Kostić-Rajačić, Slađana
PY  - 2012
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/112
AB  - Molecular modelling studies were undertaken in order to identify key interactions of selected ligands with α1A adrenergic receptor, responsible for their binding and presumably receptor activation. The previously made model of α1A adrenergic receptor was optimized by molecular dynamics and different arylpiperazine ligands were docked. The results show a high correlation to the experimentally determined binding affinities. Ligand orientations and its interactions with specific amino acid residues in the binding site explain trends in its structure-activity relationship. The key interactions for those trends are mainly aromatic, which are suggested by the calculation of their ESP surfaces.
T2  - Digest Journal of Nanomaterials and Biostructures
T1  - Modeling interactions of α1a adrenergic receptor and different arylpiperazine ligands
VL  - 7
IS  - 4
SP  - 1761
EP  - 1777
UR  - https://hdl.handle.net/21.15107/rcub_cherry_112
ER  - 

@article{
author = "Sencanski, M.V. and Šukalović, Vladimir and Došen-Mićović, Ljiljana and Šoškić, Vukić and Andrić, Deana and Roglić, Goran and Kostić-Rajačić, Slađana",
year = "2012",
abstract = "Molecular modelling studies were undertaken in order to identify key interactions of selected ligands with α1A adrenergic receptor, responsible for their binding and presumably receptor activation. The previously made model of α1A adrenergic receptor was optimized by molecular dynamics and different arylpiperazine ligands were docked. The results show a high correlation to the experimentally determined binding affinities. Ligand orientations and its interactions with specific amino acid residues in the binding site explain trends in its structure-activity relationship. The key interactions for those trends are mainly aromatic, which are suggested by the calculation of their ESP surfaces.",
journal = "Digest Journal of Nanomaterials and Biostructures",
title = "Modeling interactions of α1a adrenergic receptor and different arylpiperazine ligands",
volume = "7",
number = "4",
pages = "1761-1777",
url = "https://hdl.handle.net/21.15107/rcub_cherry_112"
}

Sencanski, M.V., Šukalović, V., Došen-Mićović, L., Šoškić, V., Andrić, D., Roglić, G.,& Kostić-Rajačić, S.. (2012). Modeling interactions of α1a adrenergic receptor and different arylpiperazine ligands. in Digest Journal of Nanomaterials and Biostructures, 7(4), 1761-1777.
https://hdl.handle.net/21.15107/rcub_cherry_112

Sencanski M, Šukalović V, Došen-Mićović L, Šoškić V, Andrić D, Roglić G, Kostić-Rajačić S. Modeling interactions of α1a adrenergic receptor and different arylpiperazine ligands. in Digest Journal of Nanomaterials and Biostructures. 2012;7(4):1761-1777.
https://hdl.handle.net/21.15107/rcub_cherry_112 .

Sencanski, M.V., Šukalović, Vladimir, Došen-Mićović, Ljiljana, Šoškić, Vukić, Andrić, Deana, Roglić, Goran, Kostić-Rajačić, Slađana, "Modeling interactions of α1a adrenergic receptor and different arylpiperazine ligands" in Digest Journal of Nanomaterials and Biostructures, 7, no. 4 (2012):1761-1777,
https://hdl.handle.net/21.15107/rcub_cherry_112 .

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 .

TY  - JOUR
AU  - Sonja, Vuckovic
AU  - Katarina, Savic Vujovic
AU  - Ivanović, Milovan
AU  - Došen-Mićović, Ljiljana
AU  - Todorović, Zoran B.
AU  - Vucetic, C.
AU  - Prostran, M.
PY  - 2012
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/1276
AB  - This study aimed at evaluating the neurotoxicity of fentanyl analogs: (+/-)-cis-3-carbomethoxy fentanyl (C) and (+/-)-trans-3-carbomethoxy fentanyl (T) in rats. C and Tare less potent (2.4-3.1 and 8.4-12.3 times, respectively) than fentanyl (F) in producing both antinociception and morphine-like neurotoxic effects: loss of pinna reflex, Straub tail, impairment of motor coordination, catalepsy, loss of corneal reflex and loss of righting reflex. All of the effects tested were dose-dependent and they were abolished by pretreatment with naloxone, nonselective antagonist of opioid receptors, indicating that they are mediated via opioid receptors. Further, F, C and T exhibited similar relative potencies in producing all tested effects, indicating that similar receptors are involved in producing antinociceptive and neurotoxic effects, most probably of mu type. By using equiantinociceptive doses, C and T produced significantly shorter duration of both antinociception and neurotoxicity than F No significant differences between therapeutic indices for F, C and T were found, indicating that these compounds are equally safe and tolerable in respect to the neurotoxic effects tested. Neurotoxicity testing presented in this paper may be useful in studying the structure-activity relationship of opioid congeners.
AB  - Cilj studije bio je da se ispita neurotoksičnost analoga fentanila: (±)-cis-3-karbometoksi fentanila (C) i (±)-trans-3-karbometoksi fentanil (T) kod pacova. C je oko 2,4-3,1, a T oko 8,4-12,3 puta manje potentan od fentanila u izazivanju antinocicepcije i morfinu-sličnih neurotoksičnih efekata u koje spadaju: refleks ušne školjke, Straub-ov rep, poremećaj motorne koordinacije, katalepsija, gubitak kornealnog refleksa i gubitak refleksa uspravljanja. Svi ispitivani efekti su dozno-zavisni i bivaju poništeni ako se u pretretmanu primeni nalokson, neselektivni antagonist opioidnih receptora, što ukazuje da se efekti odigravaju posredstvom opioidnih receptora. Dalje, F, C i T ispoljavaju sličnu relativnu jačinu u izazivanju ispitivanih efekata, što ukazuje da su slični receptori uključeni u mehanizam antinocicepcije i neurotoksičnih efekata, i to su najverovatnije μ receptori. Kad se primenjuju ekviantinociceptivne doze, C i T izazivaju značajno kraće i antinociceptivno i neurotoksično dejstvo od F. Nisu dokazane značajne razlike u terapijskim indeksima između F, C i T, što ukazuje da su ovi lekovi jednako bezbedni i podnošljivi kad su u pitanju ispitivani neurotoksični efekti. Ispitivanje neurotoksičnosti prikazano u ovom radu može biti korisno u proučavanju odnosa između strukture i aktivnosti hemijski srodnih opioida.
PB  - Veterinary Faculty, Univ Beogradu, Belgrade
T2  - Acta Veterinaria, Beograd
T1  - Neurotoxicity Evaluation of Fentanyl Analogs in Rats
T1  - Ispitivanje neurotoksičnosti analoga fentanila kod pacova
VL  - 62
IS  - 1
SP  - 3
EP  - 15
DO  - 10.2298/AVB1201003V
ER  - 

@article{
author = "Sonja, Vuckovic and Katarina, Savic Vujovic and Ivanović, Milovan and Došen-Mićović, Ljiljana and Todorović, Zoran B. and Vucetic, C. and Prostran, M.",
year = "2012",
abstract = "This study aimed at evaluating the neurotoxicity of fentanyl analogs: (+/-)-cis-3-carbomethoxy fentanyl (C) and (+/-)-trans-3-carbomethoxy fentanyl (T) in rats. C and Tare less potent (2.4-3.1 and 8.4-12.3 times, respectively) than fentanyl (F) in producing both antinociception and morphine-like neurotoxic effects: loss of pinna reflex, Straub tail, impairment of motor coordination, catalepsy, loss of corneal reflex and loss of righting reflex. All of the effects tested were dose-dependent and they were abolished by pretreatment with naloxone, nonselective antagonist of opioid receptors, indicating that they are mediated via opioid receptors. Further, F, C and T exhibited similar relative potencies in producing all tested effects, indicating that similar receptors are involved in producing antinociceptive and neurotoxic effects, most probably of mu type. By using equiantinociceptive doses, C and T produced significantly shorter duration of both antinociception and neurotoxicity than F No significant differences between therapeutic indices for F, C and T were found, indicating that these compounds are equally safe and tolerable in respect to the neurotoxic effects tested. Neurotoxicity testing presented in this paper may be useful in studying the structure-activity relationship of opioid congeners., Cilj studije bio je da se ispita neurotoksičnost analoga fentanila: (±)-cis-3-karbometoksi fentanila (C) i (±)-trans-3-karbometoksi fentanil (T) kod pacova. C je oko 2,4-3,1, a T oko 8,4-12,3 puta manje potentan od fentanila u izazivanju antinocicepcije i morfinu-sličnih neurotoksičnih efekata u koje spadaju: refleks ušne školjke, Straub-ov rep, poremećaj motorne koordinacije, katalepsija, gubitak kornealnog refleksa i gubitak refleksa uspravljanja. Svi ispitivani efekti su dozno-zavisni i bivaju poništeni ako se u pretretmanu primeni nalokson, neselektivni antagonist opioidnih receptora, što ukazuje da se efekti odigravaju posredstvom opioidnih receptora. Dalje, F, C i T ispoljavaju sličnu relativnu jačinu u izazivanju ispitivanih efekata, što ukazuje da su slični receptori uključeni u mehanizam antinocicepcije i neurotoksičnih efekata, i to su najverovatnije μ receptori. Kad se primenjuju ekviantinociceptivne doze, C i T izazivaju značajno kraće i antinociceptivno i neurotoksično dejstvo od F. Nisu dokazane značajne razlike u terapijskim indeksima između F, C i T, što ukazuje da su ovi lekovi jednako bezbedni i podnošljivi kad su u pitanju ispitivani neurotoksični efekti. Ispitivanje neurotoksičnosti prikazano u ovom radu može biti korisno u proučavanju odnosa između strukture i aktivnosti hemijski srodnih opioida.",
publisher = "Veterinary Faculty, Univ Beogradu, Belgrade",
journal = "Acta Veterinaria, Beograd",
title = "Neurotoxicity Evaluation of Fentanyl Analogs in Rats, Ispitivanje neurotoksičnosti analoga fentanila kod pacova",
volume = "62",
number = "1",
pages = "3-15",
doi = "10.2298/AVB1201003V"
}

Sonja, V., Katarina, S. V., Ivanović, M., Došen-Mićović, L., Todorović, Z. B., Vucetic, C.,& Prostran, M.. (2012). Neurotoxicity Evaluation of Fentanyl Analogs in Rats. in Acta Veterinaria, Beograd
Veterinary Faculty, Univ Beogradu, Belgrade., 62(1), 3-15.
https://doi.org/10.2298/AVB1201003V

Sonja V, Katarina SV, Ivanović M, Došen-Mićović L, Todorović ZB, Vucetic C, Prostran M. Neurotoxicity Evaluation of Fentanyl Analogs in Rats. in Acta Veterinaria, Beograd. 2012;62(1):3-15.
doi:10.2298/AVB1201003V .

Sonja, Vuckovic, Katarina, Savic Vujovic, Ivanović, Milovan, Došen-Mićović, Ljiljana, Todorović, Zoran B., Vucetic, C., Prostran, M., "Neurotoxicity Evaluation of Fentanyl Analogs in Rats" in Acta Veterinaria, Beograd, 62, no. 1 (2012):3-15,
https://doi.org/10.2298/AVB1201003V . .

TY  - JOUR
AU  - Senćanski, Milan
AU  - Ivanović, Milovan
AU  - Vuckovic, Sonja
AU  - Došen-Mićović, Ljiljana
PY  - 2011
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/1207
AB  - An automated docking procedure was applied to study the binding of a series of mu- and delta-selective ligands to ligand-specific mu- and delta-opioid receptor models. Short-time molecular dynamic simulations were used to obtain ligand-specific mu- and delta-opioid receptors from arbitrarily chosen models of the active form of these receptors. The quality of receptor model depended on the molecular volume of the ligand in the receptor-ligand complex used in the molecular dynamic simulations. Within a series of ligands of similar size (volume), the results of ligand docking to the obtained ligand-specific receptor conformation were in agreement with point mutation studies. The correlation of the calculated and the experimentally determined binding energies was improved in relation to the initial receptor conformation.
AB  - Računska metoda automatizovanog dokiranja primenjena je na vezivanje serije liganada, specifičnih za µ- i δ-receptore, za modele ovih receptora. Kratkotrajna molekulsko dinamička simulacija je korišćena za dobijanje konformacija ovih receptora koje su specifične za pojedine ligande, polazeći od slučajno izabranog modela aktiviranog receptora. Kvalitet ovako dobijenog modela receptora zavisi od molekulske zapremine liganda u ligand-receptor kompleksu korišćenog u molekulsko-dinamičkoj simulaciji. Za seriju liganda slične zapremine rezultati dokiranja su u skladu sa eksperimentalnim rezltatima mutacija aminokiselina u receptoru. Korelacija izračunatih i merenih energija vezivanja je poboljšana u odnosu na rezultate dobijene sa polaznom konformacijom receptora.
PB  - Serbian Chemical Soc, Belgrade
T2  - Journal of the Serbian Chemical Society
T1  - Modeling the ligand specific mu- and delta-opioid receptor conformations
T1  - Modelovanje konformacija µ- i δ-opioidnih receptora specifičnih za pojedine ligande
VL  - 76
IS  - 9
SP  - 1247
EP  - 1262
DO  - 10.2298/JSC110120110S
ER  - 

@article{
author = "Senćanski, Milan and Ivanović, Milovan and Vuckovic, Sonja and Došen-Mićović, Ljiljana",
year = "2011",
abstract = "An automated docking procedure was applied to study the binding of a series of mu- and delta-selective ligands to ligand-specific mu- and delta-opioid receptor models. Short-time molecular dynamic simulations were used to obtain ligand-specific mu- and delta-opioid receptors from arbitrarily chosen models of the active form of these receptors. The quality of receptor model depended on the molecular volume of the ligand in the receptor-ligand complex used in the molecular dynamic simulations. Within a series of ligands of similar size (volume), the results of ligand docking to the obtained ligand-specific receptor conformation were in agreement with point mutation studies. The correlation of the calculated and the experimentally determined binding energies was improved in relation to the initial receptor conformation., Računska metoda automatizovanog dokiranja primenjena je na vezivanje serije liganada, specifičnih za µ- i δ-receptore, za modele ovih receptora. Kratkotrajna molekulsko dinamička simulacija je korišćena za dobijanje konformacija ovih receptora koje su specifične za pojedine ligande, polazeći od slučajno izabranog modela aktiviranog receptora. Kvalitet ovako dobijenog modela receptora zavisi od molekulske zapremine liganda u ligand-receptor kompleksu korišćenog u molekulsko-dinamičkoj simulaciji. Za seriju liganda slične zapremine rezultati dokiranja su u skladu sa eksperimentalnim rezltatima mutacija aminokiselina u receptoru. Korelacija izračunatih i merenih energija vezivanja je poboljšana u odnosu na rezultate dobijene sa polaznom konformacijom receptora.",
publisher = "Serbian Chemical Soc, Belgrade",
journal = "Journal of the Serbian Chemical Society",
title = "Modeling the ligand specific mu- and delta-opioid receptor conformations, Modelovanje konformacija µ- i δ-opioidnih receptora specifičnih za pojedine ligande",
volume = "76",
number = "9",
pages = "1247-1262",
doi = "10.2298/JSC110120110S"
}

Senćanski, M., Ivanović, M., Vuckovic, S.,& Došen-Mićović, L.. (2011). Modeling the ligand specific mu- and delta-opioid receptor conformations. in Journal of the Serbian Chemical Society
Serbian Chemical Soc, Belgrade., 76(9), 1247-1262.
https://doi.org/10.2298/JSC110120110S

Senćanski M, Ivanović M, Vuckovic S, Došen-Mićović L. Modeling the ligand specific mu- and delta-opioid receptor conformations. in Journal of the Serbian Chemical Society. 2011;76(9):1247-1262.
doi:10.2298/JSC110120110S .

Senćanski, Milan, Ivanović, Milovan, Vuckovic, Sonja, Došen-Mićović, Ljiljana, "Modeling the ligand specific mu- and delta-opioid receptor conformations" in Journal of the Serbian Chemical Society, 76, no. 9 (2011):1247-1262,
https://doi.org/10.2298/JSC110120110S . .

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  - Micovic, Vuk I.
AU  - Ivanović, Milovan
AU  - Došen-Mićović, Ljiljana
PY  - 2009
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/1034
AB  - The delta-opioid receptor is sensitive to ligand geometry. In order to assist the synthesis of new delta-selective opioid ligands, the structure elements of delta-selective opioid ligands necessary for their effective binding were investigated. The automated docking procedure with a flexible ligand was used to simulate the binding of 17 delta-selective ligands to the delta-receptor. It was found that voluminous N-alkyl groups reduce the binding potency of naltrindole derivatives by preventing the ligands from adopting the preferred conformation in the receptor. This was confirmed by enantiospecific binding of chiral compounds where only one enantiomer adopts the naltrindole-like preferred conformation in the binding pocket. Voluminous groups replacing the hydroxyl group in the 3-hydroxybenzyl fragment of naltrindole analogs reduce the binding potency due to unfavorable steric interactions with the receptor. The two diastereoisomers of the potent delta-opioid ligand SNC80 confirmed the preferred binding conformation and the major receptor-ligand interactions.
PB  - Serbian Chemical Soc, Belgrade
T2  - Journal of the Serbian Chemical Society
T1  - Structural requirements for ligands of the delta-opioid receptor
VL  - 74
IS  - 11
SP  - 1207
EP  - 1217
DO  - 10.2298/JSC0911207M
ER  - 

@article{
author = "Micovic, Vuk I. and Ivanović, Milovan and Došen-Mićović, Ljiljana",
year = "2009",
abstract = "The delta-opioid receptor is sensitive to ligand geometry. In order to assist the synthesis of new delta-selective opioid ligands, the structure elements of delta-selective opioid ligands necessary for their effective binding were investigated. The automated docking procedure with a flexible ligand was used to simulate the binding of 17 delta-selective ligands to the delta-receptor. It was found that voluminous N-alkyl groups reduce the binding potency of naltrindole derivatives by preventing the ligands from adopting the preferred conformation in the receptor. This was confirmed by enantiospecific binding of chiral compounds where only one enantiomer adopts the naltrindole-like preferred conformation in the binding pocket. Voluminous groups replacing the hydroxyl group in the 3-hydroxybenzyl fragment of naltrindole analogs reduce the binding potency due to unfavorable steric interactions with the receptor. The two diastereoisomers of the potent delta-opioid ligand SNC80 confirmed the preferred binding conformation and the major receptor-ligand interactions.",
publisher = "Serbian Chemical Soc, Belgrade",
journal = "Journal of the Serbian Chemical Society",
title = "Structural requirements for ligands of the delta-opioid receptor",
volume = "74",
number = "11",
pages = "1207-1217",
doi = "10.2298/JSC0911207M"
}

Micovic, V. I., Ivanović, M.,& Došen-Mićović, L.. (2009). Structural requirements for ligands of the delta-opioid receptor. in Journal of the Serbian Chemical Society
Serbian Chemical Soc, Belgrade., 74(11), 1207-1217.
https://doi.org/10.2298/JSC0911207M

Micovic VI, Ivanović M, Došen-Mićović L. Structural requirements for ligands of the delta-opioid receptor. in Journal of the Serbian Chemical Society. 2009;74(11):1207-1217.
doi:10.2298/JSC0911207M .

Micovic, Vuk I., Ivanović, Milovan, Došen-Mićović, Ljiljana, "Structural requirements for ligands of the delta-opioid receptor" in Journal of the Serbian Chemical Society, 74, no. 11 (2009):1207-1217,
https://doi.org/10.2298/JSC0911207M . .

TY  - JOUR
AU  - Micovic, Vuk
AU  - Ivanović, Milovan
AU  - Došen-Mićović, Ljiljana
PY  - 2009
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/872
AB  - An automated docking procedure was used to study binding of a series of delta-selective ligands to three models of the delta-opioid receptor. These models are thought to represent the three ligand-specific receptor conformations. Docking results are in agreement with point mutation studies and suggest that different ligands-agonists and antagonists-may bind to the same binding site under different receptor conformations. Docking to different receptor models ( conformations) also suggests that by changing to a receptor-specific conformation, the receptor may open or close different binding sites to other ligands.
PB  - Springer, New York
T2  - Journal of Molecular Modeling
T1  - Docking studies suggest ligand-specific delta-opioid receptor conformations
VL  - 15
IS  - 3
SP  - 267
EP  - 280
DO  - 10.1007/s00894-008-0396-7
ER  - 

@article{
author = "Micovic, Vuk and Ivanović, Milovan and Došen-Mićović, Ljiljana",
year = "2009",
abstract = "An automated docking procedure was used to study binding of a series of delta-selective ligands to three models of the delta-opioid receptor. These models are thought to represent the three ligand-specific receptor conformations. Docking results are in agreement with point mutation studies and suggest that different ligands-agonists and antagonists-may bind to the same binding site under different receptor conformations. Docking to different receptor models ( conformations) also suggests that by changing to a receptor-specific conformation, the receptor may open or close different binding sites to other ligands.",
publisher = "Springer, New York",
journal = "Journal of Molecular Modeling",
title = "Docking studies suggest ligand-specific delta-opioid receptor conformations",
volume = "15",
number = "3",
pages = "267-280",
doi = "10.1007/s00894-008-0396-7"
}

Micovic, V., Ivanović, M.,& Došen-Mićović, L.. (2009). Docking studies suggest ligand-specific delta-opioid receptor conformations. in Journal of Molecular Modeling
Springer, New York., 15(3), 267-280.
https://doi.org/10.1007/s00894-008-0396-7

Micovic V, Ivanović M, Došen-Mićović L. Docking studies suggest ligand-specific delta-opioid receptor conformations. in Journal of Molecular Modeling. 2009;15(3):267-280.
doi:10.1007/s00894-008-0396-7 .

Micovic, Vuk, Ivanović, Milovan, Došen-Mićović, Ljiljana, "Docking studies suggest ligand-specific delta-opioid receptor conformations" in Journal of Molecular Modeling, 15, no. 3 (2009):267-280,
https://doi.org/10.1007/s00894-008-0396-7 . .

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  - Došen-Mićović, Ljiljana
AU  - Ivanović, Milovan
AU  - Micovic, V
PY  - 2006
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/771
AB  - Fentanyl is a highly potent and clinically widely used narcotic analgesic. The synthesis of its analogs remains a challenge in the attempt to develop highly selective p-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking in a Study of the formation of complexes between a series of active fentanyl analogs and the mu-opioid receptor is described. The optimal position and orientation Of fourteen fentanyl analogs in the binding pocket of the mu-receptor were determined. The major receptor amino acids and the ligand functional groups participating in the complex formation were identified. Stereochemical effects on the potency and binding are explained. The proposed model of ligand-receptor binding is in agreement with point mutation experiments explaining the role of the amino acids: Asp147, Tyr148, Asn230, His297, Trp318, His319, Cys321, and Tyr326 in the complex formation. In addition, the following amino acids were identified as being important for ligand binding or receptor activation: Ile322, Gly325, Val300, Met203, Leu200, Val143, and Ile144. (c) 2005 Elsevier Ltd. All rights reserved.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Bioorganic and Medicinal Chemistry
T1  - Steric interactions and the activity of fentanyl analogs at the mu-opioid receptor
VL  - 14
IS  - 9
SP  - 2887
EP  - 2895
DO  - 10.1016/j.bmc.2005.12.010
ER  - 

@article{
author = "Došen-Mićović, Ljiljana and Ivanović, Milovan and Micovic, V",
year = "2006",
abstract = "Fentanyl is a highly potent and clinically widely used narcotic analgesic. The synthesis of its analogs remains a challenge in the attempt to develop highly selective p-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking in a Study of the formation of complexes between a series of active fentanyl analogs and the mu-opioid receptor is described. The optimal position and orientation Of fourteen fentanyl analogs in the binding pocket of the mu-receptor were determined. The major receptor amino acids and the ligand functional groups participating in the complex formation were identified. Stereochemical effects on the potency and binding are explained. The proposed model of ligand-receptor binding is in agreement with point mutation experiments explaining the role of the amino acids: Asp147, Tyr148, Asn230, His297, Trp318, His319, Cys321, and Tyr326 in the complex formation. In addition, the following amino acids were identified as being important for ligand binding or receptor activation: Ile322, Gly325, Val300, Met203, Leu200, Val143, and Ile144. (c) 2005 Elsevier Ltd. All rights reserved.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Bioorganic and Medicinal Chemistry",
title = "Steric interactions and the activity of fentanyl analogs at the mu-opioid receptor",
volume = "14",
number = "9",
pages = "2887-2895",
doi = "10.1016/j.bmc.2005.12.010"
}

Došen-Mićović, L., Ivanović, M.,& Micovic, V.. (2006). Steric interactions and the activity of fentanyl analogs at the mu-opioid receptor. in Bioorganic and Medicinal Chemistry
Pergamon-Elsevier Science Ltd, Oxford., 14(9), 2887-2895.
https://doi.org/10.1016/j.bmc.2005.12.010

Došen-Mićović L, Ivanović M, Micovic V. Steric interactions and the activity of fentanyl analogs at the mu-opioid receptor. in Bioorganic and Medicinal Chemistry. 2006;14(9):2887-2895.
doi:10.1016/j.bmc.2005.12.010 .

Došen-Mićović, Ljiljana, Ivanović, Milovan, Micovic, V, "Steric interactions and the activity of fentanyl analogs at the mu-opioid receptor" in Bioorganic and Medicinal Chemistry, 14, no. 9 (2006):2887-2895,
https://doi.org/10.1016/j.bmc.2005.12.010 . .

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  - JOUR
AU  - Petrović, G.
AU  - Saičić, Radomir
AU  - Došen-Mićović, Ljiljana
AU  - Čeković, Živorad
PY  - 2004
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/668
AB  - A stereoselective free radical introduction of a phenylthio group onto a nonactivated methyl group in the 8-position, adjacent to a prochiral carbon atom, was achieved by photolysis of (-)-menthyl benzenesulfenate in the presence of hexabutylditin and (1R, 3R, 4S, 8S)-9-phenylthiomenthot (4) was obtained with 91 % optical purity. High stereoselectivity of the reaction was calculated (ab initio MP2/6-3 1G**) to be the consequence of the difference in the transition state eneregies (DeltaDeltaG(#) = 5.08 kJ/mol) favouring 4 relative to (1R,3R,4S,8R)-9-phenylthiomenthoI (5). The absolute configuration of a the new chiral carbon atom was confirmed by its correlation with the corresponding menthane-3,9-diol of known stereochemistry.
AB  - Fotolizom (–)-mentil-benzensulfenata u prisustvu heksabutil-dikalaja izvršeno je stereoselektivno uvođenje feniltio grupe na neaktiviranu metil grupu u δ-položaju koja je susedna prohiralnom ugljenikovom atomu i dobiven je (1R 3R, 4S, 8S)-9-feniltio-mentol (4) sa 91 % optičke čistoće. Visoka stereoselektivnost reakcije, potvrđena računom (ab initio MP2/6-21G**) posledica je razlike u energijama prelaznih stanja ΔΔG# = 5.08 kJ/mol) koja favorizuje nastajanje 4 u odnosu na (1R, 3R, 4S, 8R)-9-feniltio-mentol (5). Apsolutna konfiguracija novog hiralnog ugljenikovog atoma potvrđena je korelacijom s odgovarajućim mentan-3,9-diolom poznate stereohemije.
PB  - Serbian Chemical Soc, Belgrade
T2  - Journal of the Serbian Chemical Society
T1  - Stereoselective free radical phenylsulfenylation of a nonactivated delta-carbon atom
T1  - Stereoselektivno slobodnoradikalsko fenilsulfenilovanje neaktiviranog δ-ugljenikovog atoma
VL  - 69
IS  - 10
SP  - 737
EP  - 747
DO  - 10.2298/JSC0410737P
ER  - 

@article{
author = "Petrović, G. and Saičić, Radomir and Došen-Mićović, Ljiljana and Čeković, Živorad",
year = "2004",
abstract = "A stereoselective free radical introduction of a phenylthio group onto a nonactivated methyl group in the 8-position, adjacent to a prochiral carbon atom, was achieved by photolysis of (-)-menthyl benzenesulfenate in the presence of hexabutylditin and (1R, 3R, 4S, 8S)-9-phenylthiomenthot (4) was obtained with 91 % optical purity. High stereoselectivity of the reaction was calculated (ab initio MP2/6-3 1G**) to be the consequence of the difference in the transition state eneregies (DeltaDeltaG(#) = 5.08 kJ/mol) favouring 4 relative to (1R,3R,4S,8R)-9-phenylthiomenthoI (5). The absolute configuration of a the new chiral carbon atom was confirmed by its correlation with the corresponding menthane-3,9-diol of known stereochemistry., Fotolizom (–)-mentil-benzensulfenata u prisustvu heksabutil-dikalaja izvršeno je stereoselektivno uvođenje feniltio grupe na neaktiviranu metil grupu u δ-položaju koja je susedna prohiralnom ugljenikovom atomu i dobiven je (1R 3R, 4S, 8S)-9-feniltio-mentol (4) sa 91 % optičke čistoće. Visoka stereoselektivnost reakcije, potvrđena računom (ab initio MP2/6-21G**) posledica je razlike u energijama prelaznih stanja ΔΔG# = 5.08 kJ/mol) koja favorizuje nastajanje 4 u odnosu na (1R, 3R, 4S, 8R)-9-feniltio-mentol (5). Apsolutna konfiguracija novog hiralnog ugljenikovog atoma potvrđena je korelacijom s odgovarajućim mentan-3,9-diolom poznate stereohemije.",
publisher = "Serbian Chemical Soc, Belgrade",
journal = "Journal of the Serbian Chemical Society",
title = "Stereoselective free radical phenylsulfenylation of a nonactivated delta-carbon atom, Stereoselektivno slobodnoradikalsko fenilsulfenilovanje neaktiviranog δ-ugljenikovog atoma",
volume = "69",
number = "10",
pages = "737-747",
doi = "10.2298/JSC0410737P"
}

Petrović, G., Saičić, R., Došen-Mićović, L.,& Čeković, Ž.. (2004). Stereoselective free radical phenylsulfenylation of a nonactivated delta-carbon atom. in Journal of the Serbian Chemical Society
Serbian Chemical Soc, Belgrade., 69(10), 737-747.
https://doi.org/10.2298/JSC0410737P

Petrović G, Saičić R, Došen-Mićović L, Čeković Ž. Stereoselective free radical phenylsulfenylation of a nonactivated delta-carbon atom. in Journal of the Serbian Chemical Society. 2004;69(10):737-747.
doi:10.2298/JSC0410737P .

Petrović, G., Saičić, Radomir, Došen-Mićović, Ljiljana, Čeković, Živorad, "Stereoselective free radical phenylsulfenylation of a nonactivated delta-carbon atom" in Journal of the Serbian Chemical Society, 69, no. 10 (2004):737-747,
https://doi.org/10.2298/JSC0410737P . .

TY  - JOUR
AU  - Kiricojevic, VD
AU  - Ivanović, Milovan
AU  - Mićović, Ivan V.
AU  - Popović-Đorđević, Jelena
AU  - Roglić, Goran
AU  - Došen-Mićović, Ljiljana
PY  - 2002
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/529
AB  - An efficient synthesis of methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate (7) has been developed, starting from 1-benzylpiperidin-4-one (1), The compound is a key intermediate in the synthesis of new generation, highly active narcotic analgesics, such as remifentanil. as well as the novel classes of fentanyl analogues, An optimized Strecker-type condensation of piperidone 1 with aniline and HCN yielded the anilino-nitrile 2 (approximate to90%) which, upon selective hydrolysis with cone. H2SO4, gave the anilino-amide 3. After vigorous basic hydrolysis of 3, followed by acidification and successive treatment with SOCl2 and MeOH, the anilino-ester 5 was obtained (40-45%, in 3 steps). N-Acylation of 5 with propionyl chloride yielded the anilido-ester 6 (70-80%). In the final step, the catalytic N-debenzylation of 6 was examined under various conditions and optimized to yield 7 in near quantitative yields.
AB  - U ovom radu razvijena je efikasna sinteza metil 4-[(1-oksopropil)fenilamino]piperidin-4-karboksilata (7), prolazeći od 1-benzil piperidin-4-on-1 (1). Jedinjenje 7 je ključni intermedijer u sintezi nove generacije visoko aktivnih narkotičkih analgetika, kao što je remifentanil a takođe i novih klasa analoga fentanyla. U optimizovanoj Strecker-ovoj kondenzaciji priperidona 1 sa anilinom i HCN, dobijen je anilino-nitril 2 (≈90%) prinos čijom je selektivnom hidrolizom pomoću konc. H2SO4 postao anilino-amid 3. Intenzivnom baznom hidrolizom ovog intermedijera, zakišeljavanjem a zatim sukcesivno reakcijom sa SOCl2 i MeOH sintetisan je anilino-estar 5 (≈40–45% prinos u 3 faze). N-acelovanjem anilino-estra 5 sa propionil hloridom postao je anilido-estar 6 (≈70–80% prinos). U poslednjom fazi sinteze izvršena je optimizacija katalitičkog N-debenzilovanja anilido-estra 6 do finalnog proizvoda 7, u približno kvantitativnom prinosu.
PB  - Serbian Chemical Soc, Belgrade
T2  - Journal of the Serbian Chemical Society
T1  - An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate
T1  - Optimizovana sinteza značajnog farmaceutskog intermedijera metil 4-[(1-oksopropil)fenilamino]piperidin-4-karboksilata
VL  - 67
IS  - 12
SP  - 793
EP  - 802
DO  - 10.2298/JSC0212793K
ER  - 

@article{
author = "Kiricojevic, VD and Ivanović, Milovan and Mićović, Ivan V. and Popović-Đorđević, Jelena and Roglić, Goran and Došen-Mićović, Ljiljana",
year = "2002",
abstract = "An efficient synthesis of methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate (7) has been developed, starting from 1-benzylpiperidin-4-one (1), The compound is a key intermediate in the synthesis of new generation, highly active narcotic analgesics, such as remifentanil. as well as the novel classes of fentanyl analogues, An optimized Strecker-type condensation of piperidone 1 with aniline and HCN yielded the anilino-nitrile 2 (approximate to90%) which, upon selective hydrolysis with cone. H2SO4, gave the anilino-amide 3. After vigorous basic hydrolysis of 3, followed by acidification and successive treatment with SOCl2 and MeOH, the anilino-ester 5 was obtained (40-45%, in 3 steps). N-Acylation of 5 with propionyl chloride yielded the anilido-ester 6 (70-80%). In the final step, the catalytic N-debenzylation of 6 was examined under various conditions and optimized to yield 7 in near quantitative yields., U ovom radu razvijena je efikasna sinteza metil 4-[(1-oksopropil)fenilamino]piperidin-4-karboksilata (7), prolazeći od 1-benzil piperidin-4-on-1 (1). Jedinjenje 7 je ključni intermedijer u sintezi nove generacije visoko aktivnih narkotičkih analgetika, kao što je remifentanil a takođe i novih klasa analoga fentanyla. U optimizovanoj Strecker-ovoj kondenzaciji priperidona 1 sa anilinom i HCN, dobijen je anilino-nitril 2 (≈90%) prinos čijom je selektivnom hidrolizom pomoću konc. H2SO4 postao anilino-amid 3. Intenzivnom baznom hidrolizom ovog intermedijera, zakišeljavanjem a zatim sukcesivno reakcijom sa SOCl2 i MeOH sintetisan je anilino-estar 5 (≈40–45% prinos u 3 faze). N-acelovanjem anilino-estra 5 sa propionil hloridom postao je anilido-estar 6 (≈70–80% prinos). U poslednjom fazi sinteze izvršena je optimizacija katalitičkog N-debenzilovanja anilido-estra 6 do finalnog proizvoda 7, u približno kvantitativnom prinosu.",
publisher = "Serbian Chemical Soc, Belgrade",
journal = "Journal of the Serbian Chemical Society",
title = "An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate, Optimizovana sinteza značajnog farmaceutskog intermedijera metil 4-[(1-oksopropil)fenilamino]piperidin-4-karboksilata",
volume = "67",
number = "12",
pages = "793-802",
doi = "10.2298/JSC0212793K"
}

Kiricojevic, V., Ivanović, M., Mićović, I. V., Popović-Đorđević, J., Roglić, G.,& Došen-Mićović, L.. (2002). An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate. in Journal of the Serbian Chemical Society
Serbian Chemical Soc, Belgrade., 67(12), 793-802.
https://doi.org/10.2298/JSC0212793K

Kiricojevic V, Ivanović M, Mićović IV, Popović-Đorđević J, Roglić G, Došen-Mićović L. An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate. in Journal of the Serbian Chemical Society. 2002;67(12):793-802.
doi:10.2298/JSC0212793K .

Kiricojevic, VD, Ivanović, Milovan, Mićović, Ivan V., Popović-Đorđević, Jelena, Roglić, Goran, Došen-Mićović, Ljiljana, "An optimized synthesis of a key pharmaceutical intermediate methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate" in Journal of the Serbian Chemical Society, 67, no. 12 (2002):793-802,
https://doi.org/10.2298/JSC0212793K . .

TY  - JOUR
AU  - Mićović, Ivan V.
AU  - Ivanović, Milovan
AU  - Vuckovic, SM
AU  - Prostran, MS
AU  - Došen-Mićović, Ljiljana
AU  - Kiricojevic, VD
PY  - 2000
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/442
AB  - The synthesis of 4-methyl fentanyl, a prototype of a novel class of fentanyl analogues has been effected in 5 steps, starting from N-ethoxycarbonyl-4-piperidone (similar to 20% overall yield). In the key step, N-phenylation of secondary aliphatic amide intermediate was achieved by a novel reaction, using diphenyliodonium chloride for the phenyl group transfer. Preliminary pharmacological results indicate that 4-methyl fentanyl is a super potent narcotic analgesic, about four times more potent than fentanyl. (C) 2000 Elsevier Science Ltd. All rights reserved.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Bioorganic and Medicinal Chemistry Letters
T1  - The synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl
VL  - 10
IS  - 17
SP  - 2011
EP  - 2014
DO  - 10.1016/S0960-894X(00)00394-2
ER  - 

@article{
author = "Mićović, Ivan V. and Ivanović, Milovan and Vuckovic, SM and Prostran, MS and Došen-Mićović, Ljiljana and Kiricojevic, VD",
year = "2000",
abstract = "The synthesis of 4-methyl fentanyl, a prototype of a novel class of fentanyl analogues has been effected in 5 steps, starting from N-ethoxycarbonyl-4-piperidone (similar to 20% overall yield). In the key step, N-phenylation of secondary aliphatic amide intermediate was achieved by a novel reaction, using diphenyliodonium chloride for the phenyl group transfer. Preliminary pharmacological results indicate that 4-methyl fentanyl is a super potent narcotic analgesic, about four times more potent than fentanyl. (C) 2000 Elsevier Science Ltd. All rights reserved.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Bioorganic and Medicinal Chemistry Letters",
title = "The synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl",
volume = "10",
number = "17",
pages = "2011-2014",
doi = "10.1016/S0960-894X(00)00394-2"
}

Mićović, I. V., Ivanović, M., Vuckovic, S., Prostran, M., Došen-Mićović, L.,& Kiricojevic, V.. (2000). The synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl. in Bioorganic and Medicinal Chemistry Letters
Pergamon-Elsevier Science Ltd, Oxford., 10(17), 2011-2014.
https://doi.org/10.1016/S0960-894X(00)00394-2

Mićović IV, Ivanović M, Vuckovic S, Prostran M, Došen-Mićović L, Kiricojevic V. The synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl. in Bioorganic and Medicinal Chemistry Letters. 2000;10(17):2011-2014.
doi:10.1016/S0960-894X(00)00394-2 .

Mićović, Ivan V., Ivanović, Milovan, Vuckovic, SM, Prostran, MS, Došen-Mićović, Ljiljana, Kiricojevic, VD, "The synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl" in Bioorganic and Medicinal Chemistry Letters, 10, no. 17 (2000):2011-2014,
https://doi.org/10.1016/S0960-894X(00)00394-2 . .

TY  - JOUR
AU  - Mićović, Ivan V.
AU  - Ivanović, Milovan
AU  - Vuckovic, S
AU  - Jovanovic-Micic, D
AU  - Beleslin, D.
AU  - Došen-Mićović, Ljiljana
AU  - Kiricojevic, VD
PY  - 1998
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/370
AB  - A novel analogue of fentanyl, 3-carbomethoxyfentanyl, or "iso-carfentanil", was synthesized by a simple and efficient route. In the first step phenethylamine was condensed with two equivalents of methyl acrylate to afford the amino-diester Ib in quantitative yield. Dieckmann cyclization of this intermediate yielded 3-carbomethoxy N-phenethyl-4-piperidone 2 in ca. 80% yield, after mild hydrolysis. Condensation of this beta-keto ester with aniline in acetic acid gave the stable enamine 3 (70% yield) which was then reduced with NaBH3CN in methanol at pH approximate to 5, to yield 4-anilino-3-carbomethoxy-N-phenethyl piperidine, quantitatively. This intermediate was obtained as a 50:50 mixture of the (+/-) cis and (+/-) trans isomers, 4a and 4b, respectively. After the mixture of diastereoisomers was separated on a neutral aluminium oxide column, the pure 4a and 4b isomers were acylated with propionyl chloride, thus completing the synthesis of 3-carbomethoxy fentanyl 5a and 5b. The relative stereochemistry was H-1-NMR spectroscopy. These compounds present regioisomers of determined by carfentanil, one of the most potent narcotic analgesic known to date. Preliminary pharmacological evaluation (tail-withdrawal test in rats) revealed substantially reduced potency of both diastereoisomers, the (+/-) trans 5b in particular, compared to carfentanil. The computational (molecular mechanics) search of the low energy regions of the conformational space of the cis 5a and trans 5b isomers revealed the difference in their conformational mobility. Besides being more conformationaly flexible, the trans isomer has unfavorable orientation of the 4-N-phenylpropanamide group compared to the other active analogs of fentanyl. This is believed to be the reason of its reduced potency relative to fentanyl.
PB  - Serbian Chemical Soc, Belgrade
T2  - Journal of the Serbian Chemical Society
T1  - The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil"
VL  - 63
IS  - 2
SP  - 93
EP  - 112
UR  - https://hdl.handle.net/21.15107/rcub_cherry_370
ER  - 

@article{
author = "Mićović, Ivan V. and Ivanović, Milovan and Vuckovic, S and Jovanovic-Micic, D and Beleslin, D. and Došen-Mićović, Ljiljana and Kiricojevic, VD",
year = "1998",
abstract = "A novel analogue of fentanyl, 3-carbomethoxyfentanyl, or "iso-carfentanil", was synthesized by a simple and efficient route. In the first step phenethylamine was condensed with two equivalents of methyl acrylate to afford the amino-diester Ib in quantitative yield. Dieckmann cyclization of this intermediate yielded 3-carbomethoxy N-phenethyl-4-piperidone 2 in ca. 80% yield, after mild hydrolysis. Condensation of this beta-keto ester with aniline in acetic acid gave the stable enamine 3 (70% yield) which was then reduced with NaBH3CN in methanol at pH approximate to 5, to yield 4-anilino-3-carbomethoxy-N-phenethyl piperidine, quantitatively. This intermediate was obtained as a 50:50 mixture of the (+/-) cis and (+/-) trans isomers, 4a and 4b, respectively. After the mixture of diastereoisomers was separated on a neutral aluminium oxide column, the pure 4a and 4b isomers were acylated with propionyl chloride, thus completing the synthesis of 3-carbomethoxy fentanyl 5a and 5b. The relative stereochemistry was H-1-NMR spectroscopy. These compounds present regioisomers of determined by carfentanil, one of the most potent narcotic analgesic known to date. Preliminary pharmacological evaluation (tail-withdrawal test in rats) revealed substantially reduced potency of both diastereoisomers, the (+/-) trans 5b in particular, compared to carfentanil. The computational (molecular mechanics) search of the low energy regions of the conformational space of the cis 5a and trans 5b isomers revealed the difference in their conformational mobility. Besides being more conformationaly flexible, the trans isomer has unfavorable orientation of the 4-N-phenylpropanamide group compared to the other active analogs of fentanyl. This is believed to be the reason of its reduced potency relative to fentanyl.",
publisher = "Serbian Chemical Soc, Belgrade",
journal = "Journal of the Serbian Chemical Society",
title = "The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil"",
volume = "63",
number = "2",
pages = "93-112",
url = "https://hdl.handle.net/21.15107/rcub_cherry_370"
}

Mićović, I. V., Ivanović, M., Vuckovic, S., Jovanovic-Micic, D., Beleslin, D., Došen-Mićović, L.,& Kiricojevic, V.. (1998). The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil". in Journal of the Serbian Chemical Society
Serbian Chemical Soc, Belgrade., 63(2), 93-112.
https://hdl.handle.net/21.15107/rcub_cherry_370

Mićović IV, Ivanović M, Vuckovic S, Jovanovic-Micic D, Beleslin D, Došen-Mićović L, Kiricojevic V. The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil". in Journal of the Serbian Chemical Society. 1998;63(2):93-112.
https://hdl.handle.net/21.15107/rcub_cherry_370 .

Mićović, Ivan V., Ivanović, Milovan, Vuckovic, S, Jovanovic-Micic, D, Beleslin, D., Došen-Mićović, Ljiljana, Kiricojevic, VD, "The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil"" in Journal of the Serbian Chemical Society, 63, no. 2 (1998):93-112,
https://hdl.handle.net/21.15107/rcub_cherry_370 .