Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction

A. Váradi, Travis C. Palmer, Nathan Haselton, Daniel Afonin, Joan J. Subrath, Valerie Le Rouzic, Amanda Hunkele, Gavril W. Pasternak, Gina F. Marrone, Attila Borics, Susruta Majumdar

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

We report a novel approach to synthesize carfentanil amide analogues utilizing the isocyanide-based four-component Ugi multicomponent reaction. A small library of bis-amide analogues of carfentanil was created using N-alkylpiperidones, aniline, propionic acid, and various aliphatic isocyanides. Our lead compound showed high affinity for mu (MOR) and delta opioid receptors (DOR) with no appreciable affinity for kappa (KOR) receptors in radioligand binding assays. The compound was found to be a mixed MOR agonist/partial DOR agonist in [35S]GTPγS functional assays, and it showed moderate analgesic potency in vivo. The compound showed no visible signs of physical dependence or constipation in mice. In addition, it produced less respiratory depression than morphine. Most mixed MOR/DOR opioids reported in the literature are peptides and thereby systemically inactive. Our approach utilizing a multicomponent reaction has the promise to deliver potent and efficacious small-molecule analgesics with potential clinical utility.

Original languageEnglish
Pages (from-to)1570-1577
Number of pages8
JournalACS Chemical Neuroscience
Volume6
Issue number9
DOIs
Publication statusPublished - Jul 6 2015

Fingerprint

carfentanil
delta Opioid Receptor
Amides
Opioid Analgesics
Cyanides
Analgesics
Assays
Lead compounds
kappa Opioid Receptor
Radioligand Assay
mu Opioid Receptor
Constipation
Respiratory Insufficiency
Morphine
Libraries
Peptides
Molecules

Keywords

  • carfentanil
  • mu-delta
  • multicomponent reactions
  • opioid analgesics
  • Ugi reaction

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

Cite this

Váradi, A., Palmer, T. C., Haselton, N., Afonin, D., Subrath, J. J., Le Rouzic, V., ... Majumdar, S. (2015). Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction. ACS Chemical Neuroscience, 6(9), 1570-1577. https://doi.org/10.1021/acschemneuro.5b00137

Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction. / Váradi, A.; Palmer, Travis C.; Haselton, Nathan; Afonin, Daniel; Subrath, Joan J.; Le Rouzic, Valerie; Hunkele, Amanda; Pasternak, Gavril W.; Marrone, Gina F.; Borics, Attila; Majumdar, Susruta.

In: ACS Chemical Neuroscience, Vol. 6, No. 9, 06.07.2015, p. 1570-1577.

Research output: Contribution to journalArticle

Váradi, A, Palmer, TC, Haselton, N, Afonin, D, Subrath, JJ, Le Rouzic, V, Hunkele, A, Pasternak, GW, Marrone, GF, Borics, A & Majumdar, S 2015, 'Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction', ACS Chemical Neuroscience, vol. 6, no. 9, pp. 1570-1577. https://doi.org/10.1021/acschemneuro.5b00137
Váradi, A. ; Palmer, Travis C. ; Haselton, Nathan ; Afonin, Daniel ; Subrath, Joan J. ; Le Rouzic, Valerie ; Hunkele, Amanda ; Pasternak, Gavril W. ; Marrone, Gina F. ; Borics, Attila ; Majumdar, Susruta. / Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction. In: ACS Chemical Neuroscience. 2015 ; Vol. 6, No. 9. pp. 1570-1577.
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