title: An efficient synthesis of 3-OBn-6β,14-epoxy-bridged opiates from naltrexone and identification of a related dual MOR inverse agonist/KOR agonist.
abstract: In an effort to better understand the conformational preferences that inform the biological activity of naltrexone and related naltrexol derivatives, a new synthesis of the restricted analog 3-OBn-6β,14-epoxymorphinan 4 is described. 4 was synthesized starting from naltrexone in 50% overall yield, proceeding through the OBn-6α-triflate intermediate 8. Key steps to the synthesis include benzylation (96% yield), reduction (90% yield, α:β:3:2), followed by a one-pot triflation/displacement sequence (96% yield) to yield the desired bridged epoxy derivative 4. X-ray crystallographic analysis of intermediate 3-OBn-6α-naltrexol 7a supports population of the key boat conformation required for the epoxy ring closure. We also report that the 6β-mesylate 10-a high affinity opioid receptor ligand, the epimeric derivative of 11, and an analog of 12-functions as an inverse agonist at the mu opioid receptor using herkinorin pre-conditioned cells and an agonist at the kappa opioid receptor when evaluated in independent in vitro [(35)S]-GTP-γ-S assays.
authors: University of New England, College of Arts and Sciences, Chemistry & Physics Department, Biddeford, ME 04005, USA.
authors: David J
authors: DJ
authors: Martin
authors: Paul E
authors: PE
authors: FitzMorris
authors: Bo
authors: B
authors: Li
authors: Mario
authors: M
authors: Ayestas
authors: Ellicott J
authors: EJ
authors: Sally
authors: Christina M
authors: CM
authors: Dersch
authors: Richard B
authors: RB
authors: Rothman
authors: Amy M
authors: AM
authors: Deveau
mesh_terms: D018360:Crystallography, X-Ray; D054314:Drug Inverse Agonism; D008968:Molecular Conformation; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism
chemical_list: D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone