An efficient synthesis of 3-OBn-6β,14-epoxy-bridged opiates from naltrexone and identification of a related dual MOR inverse agonist/KOR agonist.
作者： David J. Martin , Paul E. FitzMorris , Bo Li , Mario Ayestas , Ellicott J. Sally
DOI: 10.1016/J.BMCL.2012.06.056
关键词:
摘要: Abstract In an effort to better understand the conformational preferences that inform biological activity of naltrexone and related naltrexol derivatives, a new synthesis restricted analog 3-OBn-6β,14-epoxymorphinan 4 is described. was synthesized starting from in 50% overall yield, proceeding through OBn-6α-triflate intermediate 8. Key steps include benzylation (96% yield), reduction (90% α:β:3:2), followed by one-pot triflation/displacement sequence yield) yield desired bridged epoxy derivative 4. X-ray crystallographic analysis 3-OBn-6α-naltrexol 7a supports population key boat conformation required for ring closure. We also report 6β-mesylate 10-a high affinity opioid receptor ligand, epimeric 11, 12-functions as inverse agonist at mu using herkinorin pre-conditioned cells kappa when evaluated independent vitro [35S]-GTP-γ-S assays.
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