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Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines

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2020
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Authors
Jevtić, Ivana
Savić Vujović, Katarina
Srebro, Dragana
Vučković, Sonja
Ivanović, Milovan D.
Kostić Rajačić, Slađana
Article (Accepted Version)
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Abstract
Background 4-Anilidopiperidine class of synthetic opioid analgesics, with it’s representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of μ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity.Methods The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test.Results The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In ad...dition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test.Conclusion Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.

Keywords:
Opioid / Fentanyl / Antinociceptive / Anilidopiperidine
Source:
Pharmacological Reports, 2020
Publisher:
  • Springer Nature
Funding / projects:
  • Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200026 (University of Belgrade, Institute of Chemistry, Technology and Metallurgy - IChTM) (RS-200026)
  • Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200110 (University of Belgrade, Faculty of Medicine) (RS-200110)
Note:
  • This is the peer-reviewed version of the article: Jevtić, I.I., Savić Vujović, K., Srebro, D. et al. Synthesis and pharmacological evaluation of novel cis and trans 3-substituted anilidopiperidines. Pharmacol. Rep (2020), https://doi.org/10.1007/s43440-020-00121-2
  • The published version: http://cer.ihtm.bg.ac.rs/handle/123456789/3591

DOI: 10.1007/s43440-020-00121-2

ISSN: 1734-1140

PubMed: 32613543

WoS: 000547634000001

Scopus: 2-s2.0-85087288966
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URI
https://cer.ihtm.bg.ac.rs/handle/123456789/3591
https://cer.ihtm.bg.ac.rs/handle/123456789/3592
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
IHTM
TY  - JOUR
AU  - Jevtić, Ivana
AU  - Savić Vujović, Katarina
AU  - Srebro, Dragana
AU  - Vučković, Sonja
AU  - Ivanović, Milovan D.
AU  - Kostić Rajačić, Slađana
PY  - 2020
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3591
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3592
AB  - Background 4-Anilidopiperidine class of synthetic opioid analgesics, with it’s representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of μ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity.Methods The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test.Results The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In addition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test.Conclusion Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.
PB  - Springer Nature
T2  - Pharmacological Reports
T1  - Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines
DO  - 10.1007/s43440-020-00121-2
ER  - 
@article{
author = "Jevtić, Ivana and Savić Vujović, Katarina and Srebro, Dragana and Vučković, Sonja and Ivanović, Milovan D. and Kostić Rajačić, Slađana",
year = "2020",
abstract = "Background 4-Anilidopiperidine class of synthetic opioid analgesics, with it’s representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of μ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity.Methods The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test.Results The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In addition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test.Conclusion Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.",
publisher = "Springer Nature",
journal = "Pharmacological Reports",
title = "Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines",
doi = "10.1007/s43440-020-00121-2"
}
Jevtić, I., Savić Vujović, K., Srebro, D., Vučković, S., Ivanović, M. D.,& Kostić Rajačić, S.. (2020). Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines. in Pharmacological Reports
Springer Nature..
https://doi.org/10.1007/s43440-020-00121-2
Jevtić I, Savić Vujović K, Srebro D, Vučković S, Ivanović MD, Kostić Rajačić S. Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines. in Pharmacological Reports. 2020;.
doi:10.1007/s43440-020-00121-2 .
Jevtić, Ivana, Savić Vujović, Katarina, Srebro, Dragana, Vučković, Sonja, Ivanović, Milovan D., Kostić Rajačić, Slađana, "Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines" in Pharmacological Reports (2020),
https://doi.org/10.1007/s43440-020-00121-2 . .

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