Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2,9beta-Dimethyl-2'-hydroxy-6,7-benzomorphan (18) has been synthesized from m-methoxyphenylacetone (6a) or m-methoxyphenylacetonitrile (1) via bromo-alpha-tetralone (10). Isomeric bromo-alpha-tetralone 9, instead of undergoing cyclization to a 6,7-benzomorphan, gave aromatization product 12. The structures and stereochemical assignments of 9, 10 (and thus 7 and 8), and 18 follow from analogy and from NMR data of 9, 10, 17, and 18. Compound 18 and the deoxy analog 16 are as potent as morphine and codeine, respectively, as analgetics (mice) and are without physical dependence capacity (monkeys).
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PMID:Synthesis and pharmacology of 5-noralkyl-9beta-methyl-6,7-benzomorphans and stereochemistry of some intermediates. 80 10

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 Monkey studies with the 9-demethyl homologues confirmed earlier results showing that (+)-1, suppressing abstinence in withdrawn animals, has high physical dependence capacity, while (-)-1 has none.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.
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PMID:Racemic and optically active 2,9-dimethyl-5-(m-hydroxyphenyl)morphans and pharmacological comparison with the 9-demethyl homologues. 670 55