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

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2020
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
Projects:
  • Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 451-03-68/2020-14/200026 (University of Belgrade, Institute of Chemistry, Technology and Metallurgy - IChTM) (RS-200026)
  • Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 451-03-68/2020-14/200110 (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
http://cer.ihtm.bg.ac.rs/handle/123456789/3591
http://cer.ihtm.bg.ac.rs/handle/123456789/3592
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IHTM

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