Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction

Váradi, András and Palmer, Travis C. and Haselton, Nathan and Afonin, Daniel and Subrath, joan J, and Borics, Attila (2015) Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction. ACS CHEMICAL NEUROSCIENCE, 6 (9). pp. 1570-1577. ISSN 1948-7193

Preview

Text VaradiACSChemNeuroscimanu.pdf Download (638kB) | Preview

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 [S-35]GTP gamma S 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.

Actions (login required)

Edit Item