Synthesis of carfentanil amide opioids using the Ugi multicomponent reaction Journal Article
| Authors: | Váradi, A.; Palmer, T. C.; Haselton, N.; Afonin, D.; Subrath, J. J.; Le Rouzic, V.; Hunkele, A.; Pasternak, G. W.; Marrone, G. F.; Borics, A.; Majumdar, S. |
| Article Title: | Synthesis of carfentanil amide opioids using the Ugi multicomponent reaction |
| 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. © 2015 American Chemical Society. |
| Keywords: | opioid analgesics; multicomponent reactions; carfentanil; mu-delta; ugi reaction |
| Journal Title: | ACS Chemical Neuroscience |
| Volume: | 6 |
| Issue: | 9 |
| ISSN: | 1948-7193 |
| Publisher: | American Chemical Society |
| Date Published: | 2015-09-16 |
| Start Page: | 1570 |
| End Page: | 1577 |
| Language: | English |
| DOI: | 10.1021/acschemneuro.5b00137 |
| PROVIDER: | scopus |
| PUBMED: | 26148793 |
| PMCID: | PMC4641535 |
| DOI/URL: | |
| Notes: | Export Date: 2 October 2015 -- Source: Scopus |
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