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 [(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.
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: András
authors.initials: A
authors.lastname: Váradi
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Travis C
authors.initials: TC
authors.lastname: Palmer
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Nathan
authors.initials: N
authors.lastname: Haselton
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Afonin
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Subrath
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Valerie
authors.initials: V
authors.lastname: Le Rouzic
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Amanda
authors.initials: A
authors.lastname: Hunkele
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Gina F
authors.initials: GF
authors.lastname: Marrone
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , Temesvári krt. 62, Szeged, Hungary H-6726.
authors.forename: Attila
authors.initials: A
authors.lastname: Borics
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Susruta
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005283:Fentanyl / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009020:Morphine / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012119:Respiration / Q000187:drug effects
chemical_list: D000577:Amides; D000701:Analgesics, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009020:Morphine; C017114:carfentanil; D005283:Fentanyl
keywords: Ugi reaction; carfentanil; mu-delta; multicomponent reactions; opioid analgesics