期刊
ACS CHEMICAL NEUROSCIENCE
卷 6, 期 9, 页码 1570-1577出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.5b00137
关键词
Ugi reaction; multicomponent reactions; mu-delta; opioid analgesics; carfentanil
资金
- National Institute on Drug Abuse [DA034106, DA06241]
- National Science Foundation [DGE-1257284]
- European Union
- State of Hungary - European Social Fund [TAMOP 4.2.4. A/2-11-1-2012-0001]
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.
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