codeine and Morphine-Dependence

A series of 8-alkyl-3-methoxy-17-methylmorphinan-6-ones (3C) and -isomorphinan-6-ones (3T) were prepared by conjugate addition of lithium dialkylcuprates to the corresponding 7,8-didehydro-6-ones 2C and 2T. These 17-methyl compounds were potent analgesics and were converted to mixed narcotic agonists-antagonists 7-10, by replacement of the 17-methyl groups with cycloalkylmethyl moieties. The 8 substituent modified the type of activity observed. One of these compounds, 17-(cyclobutylmethyl)-3-hydroxy-8 beta-methylmorphinan-6-one (10Ca), had an agonist-antagonist ratio of 0.1. Compound 10Ca did not support or cause dependence in rats. This compound, however, appeared to be a typical narcotic agent in morphine-dependent monkeys.

Topics: Acetates; Analgesics; Animals; Haplorhini; Humans; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Rats; Reaction Time; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders

3,6-Dimethoxy-7 beta, 17-dimethyl-4-hydroxy-5,6,8,14-tetradehydromorphinan (2) was converted to the 4-deoxy compound 4 and hydrolyzed to a mixture of the B/C-cis (C series) and B/C-trans (T series) isomers of 7,8-didehydromorphinan-6-one, 5. Hydrogenation of the separated isomers gave 7-methyl-6-oxo derivatives 6a. 7,8-Dimethyl-(6b) or 7-methyl-8-ethylmorphinan-6-one (6c) was prepared by reaction of 5 with lithium organocuprates. The analgesic N-methyl compounds 6 were converted to 17-(cyclopropylmethyl) or 17-(cyclobutylmethyl) derivatives 10--13. Some of these compounds had mixed profiles of narcotic agonist-antagonist effects. Studies with drug-dependent monkeys indicated that several of these compounds with an analgesic-antagonist ratio of less than 0.4 substitute for morphine.

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Humans; Morphinans; Morphine Dependence; Narcotic Antagonists; Substance Withdrawal Syndrome

1,2,3,4,5,6-Hexahydro-1,6-methano-3-benzazocine (1) has been synthesized via a four-step sequence from benzo-norbornadiene. This compound and its N-methyl derivative are more active than codeine in the mouse hot-plate antinociceptive assay and will not suppor morphine dependence in Rhesus monkeys.

Topics: Analgesics; Animals; Azocines; Haplorhini; Humans; Macaca mulatta; Mice; Morphine Dependence; Reaction Time; Substance Withdrawal Syndrome

The levo and dextro isomers of 2,5-dimethyl-2'-hydroxy-9alpha- and -9beta-propyl-6,7-benzomorphans have been prepared. The analgesic potency and physical dependence capacity of the optical isomers and their racemic parents were determined. The 9alpha-propyl levo isomer was analgesically equipotent with morphine; the 9beta-propyl levo isomer was considerably more potent subcutaneously and equipotent orally. None of the optical isomers suppressed the withdrawal syndrome; the 9beta-propyl levo isomer exacerbated the withdrawal syndrome.

Topics: Analgesics; Animals; Benzomorphans; Haplorhini; Humans; Mice; Morphinans; Morphine Dependence; Optical Rotation; Stereoisomerism; Substance-Related Disorders