- An efficient synthesis of 3-OBn-6β,14-epoxy-bridged opiates from naltrexone and identification of a related dual MOR inverse agonist/KOR agonist
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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.
- Martin, David J.,Fitzmorris, Paul E.,Deveau, Amy M.,Li, Bo,Ayestas, Mario,Sally, Ellicott J.,Dersch, Christina M.,Rothman, Richard B.
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- Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent
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Background: One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a
- Baynard, Caroline,Butelman, Eduardo R.,Hedrick, Sidnee L.,Horn, Jamie,Jackson, Karen,Kaska, Sophia,Kreek, Mary Jeanne,Leggas, Markos,Luo, Dan,Niloy, Kumar Kulldeep,Prisinzano, Thomas E.,Sarma, Rupam
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- Synthesis and opioid receptor affinity of a series of aralkyl ethers of 6α- and 6β-naltrexol
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A series of 6-O-ethers of 6β- and 6α-naltrexol (6 and 7) were prepared to examine the effect of large aralkyl groups on affinity of the ligands for opioid receptors. The affinities of the 6β-and 6α-O-ether with benzyl, biphenylmethyl, 1- and 2-naphthylmet
- Nelson,Davis,Nelson
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p. 4270 4277
(2007/10/02)
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