Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction
| Autor: | Travis C. Palmer, Gavril W. Pasternak, Nathan Haselton, András Váradi, Valerie Le Rouzic, Joan J. Subrath, Attila Borics, Susruta Majumdar, Amanda Hunkele, Gina F. Marrone, Daniel Afonin |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Agonist Physiology medicine.drug_class Stereochemistry Cognitive Neuroscience Isocyanide Drug Evaluation Preclinical Receptors Opioid mu Pain Physical dependence Molecular Dynamics Simulation Biochemistry Article Carfentanil Mice chemistry.chemical_compound In vivo Receptors Opioid delta Amide medicine Animals Dose-Response Relationship Drug Molecular Structure Morphine Chemistry Respiration Cell Biology General Medicine Amides Analgesics Opioid Fentanyl Molecular Docking Simulation Opioid Ugi reaction medicine.symptom medicine.drug |
| Zdroj: | ACS Chemical Neuroscience. 6:1570-1577 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.5b00137 |
| Popis: | 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 [(35)S]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. |
| Databáze: | OpenAIRE |
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