morphine and Morphine-Dependence

A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3'-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1'- and/or 4'-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6'- and/or 7'-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca(2+) increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6'-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands.

Topics: Animals; CHO Cells; Cricetulus; Drug Design; Humans; Isoquinolines; Ligands; Mice; Molecular Dynamics Simulation; Morphinans; Morphine Dependence; Narcotic Antagonists; Receptors, Opioid, mu; Structure-Activity Relationship

A large-scale, prospective drug screening of newborns by meconium analysis was done to determine more accurately the prevalence and epidemiologic characteristics of drug use in a high-risk urban, obstetric population. Every other neonate delivered in a perinatal center from November 1988 to September 1989 was prospectively enrolled and their meconium was analyzed by radioimmunoassay for the metabolites of three commonly abused drugs--cocaine, morphine (opiates), and cannabinoid. In 3010 subjects studied, 44% were positive for cocaine, morphine, or cannabinoid; 31% were positive for cocaine, 21% for morphine, and 12% for cannabinoid. In contrast, only 335 (11%) mothers admitted to illicit drug use: 52% of their newborns had a positive urine drug screen and 88% had a positive meconium drug screen. Prevalence of drug use among the pregnant women varied per month. A profile of the pregnant addict in the population studied was noted (P less than .001): service patient, single, multigravid (greater than 3), and little or no prenatal care. The major problems associated with drug use during pregnancy were principally noted in the group that was exposed to cocaine and opiates and in the group where the mothers admitted to the use of illicit drugs. On the other hand, a large number of neonates who have been exposed to drugs in utero, particularly those whose mothers denied the use of drugs, appear normal at birth and may not be recognized. Improved detection of these newborns at risk can be achieved with a high index of suspicion and meconium drug analysis.

Topics: Cannabis; Cocaine; Female; Humans; Infant, Newborn; Marijuana Abuse; Mass Screening; Meconium; Morphine; Morphine Dependence; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Prevalence; Prospective Studies; Sensitivity and Specificity; Substance-Related Disorders; United States

N-Ethyl-, N-(2-fluoroethyl)-, N-(2,2-difluoroethyl)-, and N-(2,2,2-trifluoroethyl)-substituted normeperidine (1b-e) and normetazocine (2b-e) derivatives were prepared. The analgesic activities of the compounds were determined in mice. Opiate receptor binding studies, in the presence and absence of sodium ion, were carried out. The antagonist activities of normetazocine derivatives were studied in monkeys. These were further examined in the isolated guinea pig ileum for relative agonist activity. The pKa values were measured; in vivo agonist acitivty was lost with weakly basic derivatives. For the normetazocine derivatives, opiate receptor binding data were consistent with guinea pig ileum agonist potency and mouse vas deferens antagonist potency but not with in vivo data. Opiate receptor binding was reduced for the less basic normetazocine derivatives. In the normeperidine series, there was no apparent direct relationship between pKa and opiate receptor binding. However, a relationship involving the hydrophobic character of the N-substituent is discussed. The N-(2-fluoroethyl) derivatives in both series were found to cause convulsions in rats at doses of 40-45 mg/kg ip. Elevated serum citrate levels were found in these rats, implicating in vivo oxidative deamination of the N-(fluoroalkyl) substituent to fluoroacetate.

Topics: Analgesics, Opioid; Animals; Benzomorphans; Guinea Pigs; Haplorhini; Humans; Male; Meperidine; Mice; Morphinans; Morphine Dependence; Narcotic Antagonists; Rats; Receptors, Opioid; Seizures; Structure-Activity Relationship; Substance Withdrawal Syndrome

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

The distribution of morphine in various tissues of 6 addicted monkey fetuses and in 2 infants of drug-dependent mothers (IDDM) show that significant concentrations of the drug are in the gastrointestines (tissue plus content), liver, cerebellum, lungs, heart, spleen and thymus. The high concentration of morphine in the gastrointestinal tract may be secondary to the excretion of the drug through the bile or by the repeated swallowing by the fetus of amniotic fluid which contains morphine (1.9 +/- 1.0 micrograms/dl). Meconium, taken from 2 IDDMs show a significant concentration of morphine for up to 2-3 days after birth. Thus, meconium is a useful material to analyze postnatally for the diagnosis of neonatal narcotic addiction.

Topics: Animals; Brain; Digestive System; Female; Fetus; Humans; Infant, Newborn; Macaca mulatta; Meconium; Morphine; Morphine Dependence; Pregnancy; Tissue Distribution

The N-(2-cyanoethyl)-9alpha-ethyl-5-methyl-6,7-benzomorphan (1c) is a more potent antinociceptive and has stronger receptor binding affinity than its N-methyl analogue 1b. The N-(2-cyanoethyl)-4-phenylpiperidine compounds 2b and 3b were almost inactive compared to their N-methyl congeners 2a and 3a, respectively. It appears that the pharmacological effect of the N-(2-cyanoethyl) moiety is dependent on the opioid on which it is substituted.

Topics: Analgesics; Animals; Benzomorphans; Binding, Competitive; Brain; Dihydromorphine; Haplorhini; Humans; In Vitro Techniques; Macaca mulatta; Meperidine; Mice; Morphinans; Morphine Dependence; Nitriles; Piperidines; Rats; Structure-Activity Relationship

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

2,9alpha-Dimethyl-2'-hydroxy-6,7-benzomorphan (14) has been synthesized in six to seven steps from trans-3,4-dihydro-4-(2-dimethylaminoethyl)-6-methoxy-3-methyl-1(2H)-naphthalenone (1). The key reaction of the sequence was mercuric acetate cyclization of trans-1,2-dihydro-1-(2-methylaminoethyl)-7-methoxy-2-methylnaphthalene (8) which gave a mixture of 9alpha-methyl-8alpha-hydroxy-6,7-benzomorphan (9, 49%), the corresponding acetate (10, 13%), and the 9beta-methyl-8alpha-hydroxy-6,7-benzomorphan (11, 5%). In the presence of Et3N, the yields were 16, 37, and 0%, respectively. Structural assignments are based on ir, NMR, and mass spectral data and on chemical conversions.

Topics: Analgesics; Animals; Benzomorphans; Haplorhini; Humans; Male; Mice; Molecular Conformation; Morphinans; Morphine Dependence; Reaction Time; Stereoisomerism; Structure-Activity Relationship; Substance Withdrawal Syndrome

Topics: 2-Naphthylamine; Analgesics; Animals; Bridged-Ring Compounds; Haplorhini; Humans; Macaca mulatta; Molecular Conformation; Morphine; Morphine Dependence; Naphthalenes; Optical Rotation; Rats; Reaction Time; Stereoisomerism; Structure-Activity Relationship