An efficient synthesis of 3-OBn-6β,14-epoxy-bridged opiates from naltrexone and identification of a related dual MOR inverse agonist/KOR agonist

• Published in: Bioorganic & medicinal chemistry letters 2012-11, Vol.22 (22), p.6801-6805
• Main Authors: Martin, David J., FitzMorris, Paul E., Li, Bo, Ayestas, Mario, Sally, Ellicott J., Dersch, Christina M., Rothman, Richard B., Deveau, Amy M.
• Format: Article
• Language: English
• Subjects: 6β,14-Epoxymorphinan; agonists; Antagonist; bioactive properties; Biological and medical sciences; boats; chemistry; Conformation; Crystallography, X-Ray; Drug Inverse Agonism; epoxides; Inverse Agonist; Medical sciences; Molecular Conformation; Naltrexol; Naltrexone; Naltrexone - analogs & derivatives; Naltrexone - chemical synthesis; Naltrexone - chemistry; Naltrexone - metabolism; Opiate; Pharmacology. Drug treatments; Protein Binding; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Rigid analog; X-ray diffraction
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.06.056

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 [35S]-GTP-γ-S assays.