Racemic and optically active 2,9-dimethyl-5-(m-hydroxyphenyl)morphans and pharmacological comparison with the 9-demethyl homologues.
2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan (3a) has been synthesized from 5-(m-methoxyphenyl)-2-methyl-9-oxomorphan (4) and resolved into its enantiomers (+)-3a and (-)-3a. The assigned alpha-orientation of the 9-methyl group was derived from studies of induced NMR shifts using Eu(fod)3-d27. Compound (+)-3a has inappreciable agonist (antinociceptive) activity in mice, and (-)-3a shows codeine-like potency in the hot-plate and writhing tests only. The 9-demethyl homologues, (+)-1 and (-)-1, are strong agonists, about as potent as morphine in these tests as well as in the tail-flick assay. The racemic compound 3a and (+)-3a, but not (-)-3a, exhibit low-potency, narcotic-antagonist activity in mice (tail-flick test, vs. morphine). All three, however, precipitate abstinence in nonwithdrawn, morphine-dependent rhesus monkeys. Monkey studies with the 9-demethyl homologues confirmed earlier results showing that (+)-1, suppressing abstinence in withdrawn animals, has high physical dependence capacity, while (-)-1 has none. Instead, (-)-1 precipitates abstinence in nonwithdrawn animals. Studies in rats and isolated organs (guinea pig ileum and mouse vas deferens) and receptor-binding assays confirm the quite different opioid-action profiles of (+)-1 and (-)-1, which thus might interact with different opioid receptors. Catalytic hydrogenation of the methiodide (7) of 5 gave, instead of the expected epimer of 3a, ring-opened compound 8.
D000698:Analgesia; D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D001681:Biological Assay; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009019:Morphinans / Q000138:chemical synthesis* / Q000494:pharmacology; D009904:Optical Rotation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D007202:Indicators and Reagents; D009019:Morphinans; C040990:2,9-dimethyl-5-(3-hydroxyphenyl)morphan