title: Synthesis and biological evaluation of 14-alkoxymorphinans. 1. Highly potent opioid agonists in the series of (-)-14-methoxy-N-methylmorphinan-6-ones.
abstract: A series of eight (-)-14-methoxymorphinan-6-ones was synthesized and biologically evaluated. The morphinanones 3-7 were prepared from 3-desoxy-7,8-dihydro-14-hydroxymorphinone (1). The key step in this synthetic sequence, O-methylation in position 14, was accomplished with dimethyl sulfate. Hydrolysis followed by reductive opening of the 4,5-oxygen bridge afforded the phenol 4, which was O-methylated to give 5. Removal of the 4-OH group yielded the aromatic unsubstituted morphinan 7. The synthesis of 9 and 10 was accomplished by starting from 14-methoxy-7,8-dihydrocodeinone and involved a similar reaction sequence. The compounds 12-15 were synthesized from oxymorphone (11), which was 3-O-benzylated, 6,14-bis-O-methylated with dimethyl sulfate, hydrolyzed, and hydrogenated to yield the oxymorphone 14-O-methyl ether 15. The derivatives 3, 4, 5, 7, 9, 10, 14, and 15 exhibited high antinociceptive potency in the hot-plate assay in mice, after both subcutaneous and oral administration. The most potent derivative in this series (15) showed a potency (sc) about 400 times higher than that of morphine and about 40 times higher than its 14-OH analogue oxymorphone (11). The 14-OCH3 series also exhibited a considerably higher affinity to opioid receptors in binding studies using [3H]naloxone as ligand when compared to their 14-OH analogues.
mesh_terms: D000698:Analgesia; D000818:Animals; D001667:Binding, Competitive; D001681:Biological Assay; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007202:Indicators and Reagents; D051379:Mice; D009019:Morphinans / Q000138:chemical synthesis*; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000378:metabolism; D009292:Narcotic Antagonists / Q000138:chemical synthesis*; D011817:Rabbits; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D012119:Respiration / Q000187:drug effects; D013329:Structure-Activity Relationship; D013375:Substance Withdrawal Syndrome
chemical_list: D007202:Indicators and Reagents; D009019:Morphinans; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009270:Naloxone; D009020:Morphine