thebaine and oripavine

The dependence potential of thebaine is at least partially attributed to oripavine which is one of the principal metabolites of thebaine. The analgesic potency of oripavine in mice is found to be much higher than that of thebaine and comparable to morphine. The reinforcing effect of this substance also appears to be more potent than thebaine. In rats the physical dependence potential of oripavine at a dose of 4 mg/kg is almost comparable to that of morphine at 0.5 mg/kg. Studies carried out on monkeys show that oripavine possesses weak morphine-antagonist properties. Further pharmacological studies of the metabolites of thebaine are recommended.

Topics: Animals; Humans; Macaca mulatta; Mice; Rats; Reinforcement, Psychology; Self Administration; Substance-Related Disorders; Thebaine

A whole cell

Topics: Codeine; Escherichia coli; Morphine; Thebaine

Topics: Adult; Dermatitis, Allergic Contact; Dermatitis, Occupational; Drug Industry; Humans; Male; Narcotics; Patch Tests; Thebaine

In this paper, we report a case of misidentification of medicinal plants involving dried petals of Papaver rhoeas (red poppy) contaminated with Papaver bracteatum (scarlet poppy) petals. Preliminary TLC analysis indicated the presence of thebaine either in the fluid extracts or in the petals. It was therefore necessary to carry out an accurate botanic examination of the plant material, which revealed contamination of the red poppy petals with scarlet poppy petals. Moreover, to confirm the adulteration, we developed and validated an efficient, reversed-phase ion pair HPLC method for determination of the alkaloids specific for the Papaver species. Six petal batches and five commercial fluid extracts were analyzed. Only one petal batch from Iran contained thebaine and its analogue oripavine while the alkaloids typical for the Papaver bracteatum species were identified in all fluid extracts, meaning that they were all prepared with contaminated petals.

Topics: Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Drug Contamination; Europe; Flowers; Iran; Papaver; Plant Extracts; Species Specificity; Thebaine

Further investigations into the direct synthesis of N-nororipavine from oripavine using iron powder under non-classical Polonovski conditions have been conducted. The stoichiometry, solvents and iron oxidation rates were found to have a dramatic effect on the rate of N-demethylation as well as product yield. Herein, we also present high-yield access to the N-demethylated product simply by employing stainless steel rather than iron powder as redox catalyst. To our knowledge, this is the first time stainless steel has been used to moderate the redox chemistry of iron in organic synthesis.

Topics: Catalysis; Iron; Methylation; Molecular Structure; Oxidation-Reduction; Stainless Steel; Thebaine

Buprenorphine was synthesized from oripavine by a sequence involving the conversion of oripavine into its cyclopropylmethyl quaternary salt, N-demethylation with thiolate to N-cyclopropylmethyl nororipavine, and conversion of this material to the title compound by previously available methods. The new synthesis avoids toxic reagents used previously, is shorter, and proceeds in comparable yields. Experimental and spectral data are provided for all new compounds.

Topics: Buprenorphine; Cyanogen Bromide; Green Chemistry Technology; Methylation; Nitrogen; Salts; Thebaine

Despite being studied for over 30 years, a consensus structure-activity relationship (SAR) that encompasses the full range peptidic and nonpeptidic μ-opioid receptor ligands is still not available. To achieve a consensus SAR the Conformationally Sampled Pharmacophore (CSP) method was applied to develop a predictive model of the efficacy of μ-opioid receptor ligands. Emphasis was placed on predicting the efficacy of a wide range of agonists, partial agonists, and antagonists as well as understanding their mode of interaction with the receptor. Inclusion of all accessible conformations of each ligand, a central feature of the CSP method, enabled structural features between diverse μ-opioid receptor ligands that dictate efficacy to be identified. The models were validated against a diverse collection of peptidic and nonpeptidic ligands, including benzomorphans, fentanyl (4-anilinopiperidine), methadone (3,3-diphenylpropylamines), etonitazene (benzimidazole derivatives), funaltrexamine (C6-substituted 4,5-epoxymorphinan), and herkinorin. The model predicts (1) that interactions of ligands with the B site, as with the 19-alkyl substituents of oripavines, modulate the extent of agonism; (2) that agonists with long N-substituents, as with fentanyl and N-phenethylnormorphine, can bind in an orientation such that the N substitutent interacts with the B site that also allows the basic N-receptor Asp interaction essential for agonism; and (3) that the μ agonist herkinorin, that lacks a basic nitrogen, binds to the receptor in a manner similar to the traditional opioids via interactions mediated by water or a ion. Importantly, the proposed CSP model can be reconciled with previously published SAR models for the μ receptor.

Topics: Ligands; Molecular Dynamics Simulation; Peptides; Protein Structure, Tertiary; Receptors, Opioid, mu; Structure-Activity Relationship; Thebaine

To investigate possible pharmacological mechanisms underlying the antinociceptive effect of and tolerance to N-methyl-7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydronororipavine (030418), a derivative of thienorphine.. The binding affinity and efficacy of 030418 were determined using receptor binding and guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) assays in CHO-μ, CHO-κ, CHO-δ, and CHO-ORL1 cell membranes. The analgesic activity of and tolerance to 030418 were evaluated in thermal nociceptive tests in mice. The effects of 030418 on opioid receptors were further investigated using in vivo pharmacological antagonist blockade and in vitro tissue preparations.. The compound 030418 displayed high binding affinity to all subtypes of opioid receptors with K(i) values in the nanomolar range. In [(35)S]GTPγS binding assay, the maximal stimulation of 030418 to μ-, κ-, δ-receptors and the ORL1 receptor was 89%, 86%, 67% and 91%, respectively. In hot-plate test, the antinociceptive effect of 030418 was more potent and longer than morphine. The nonselective opioid receptor antagonist naloxone could completely block 030418-induced antinociception, while both the μ-opioid receptor antagonist β-FNA and the κ-opioid receptor antagonist nor-BNI attenuated 030418-induced antinociception. In contrast, the ORL1 receptor antagonist J-113397 enhanced the antinociceptive effect of 030418. Additionally, chronic treatment with 030418 resulted in a dramatic development of tolerance that could not be effectively prevented by J-113397. In guinea pig ileum preparation, the existing action of 030418 could be removed with difficulty after prolonged washing.. The compound 030418 is a novel agonist of opioid receptors with high efficiency, long-lasting effect and liability to tolerance, which may be closely correlated with the methyl group at the N(17) position and the high hydrophobicity of the C(7)-thiophene group in its chemical structure.

Topics: Analgesics; Animals; Buprenorphine; CHO Cells; Cricetinae; Drug Tolerance; Female; Guinea Pigs; Male; Mice; Nociception; Pain Measurement; Receptors, Opioid; Thebaine

Under Polonovski-type conditions, ferrocene has been found to be a convenient and efficient catalyst for the N-demethylation of a number of N-methyl alkaloids such as opiates and tropanes. By judicious choice of solvent, good yields have been obtained for dextromethorphan, codeine methyl ether, and thebaine. The current methodology is also successful for the N-demethylation of morphine, oripavine, and tropane alkaloids, producing the corresponding N-nor compounds in reasonable yields. Key pharmaceutical intermediates such oxycodone and oxymorphone are also readily N-demethylated using this approach.

Topics: Alkaloids; Catalysis; Ferrous Compounds; Metallocenes; Methylation; Morphine; Thebaine

This paper describes the determination of opiate alkaloids (morphine, codeine, oripavine and thebaine) in industrial process liquors using capillary zone electrophoresis with UV-absorption detection at 214 nm. A study of cyclodextrin type and concentration revealed that the addition of 30 mM hydroxypropyl-beta-cyclodextrin to the electrolyte solution (100mM Tris adjusted to pH 2.8) was suitable to resolve the four analytes of interest. Typical analysis time was 12 min and the limit of detection for each alkaloid was 2.5 x 10(-6) M. The results for the proposed methodology were in good agreement with those of a conventional HPLC procedure. Under the same conditions, short-end injection was used to reduce the effective separation length from 41.5 to 8.5 cm, which allowed the determination of morphine and thebaine in process liquors within 2.5 min.

Topics: Alkaloids; Analgesics, Opioid; Capillary Electrochromatography; Chromatography, High Pressure Liquid; Codeine; Cyclodextrins; Indicators and Reagents; Morphine; Solvents; Spectrophotometry, Ultraviolet; Thebaine

A new series of ligands has been synthesized where the cinnamoyl group of the 14-cinnamoylamino morphinones has been introduced to the 7alpha-substituent of the 6,14-bridged oripavine series. In vitro the compounds were mostly low efficacy partial agonists or antagonists with some selectivity for the mu opioid receptor, with evidence of micro efficacy in vivo. The similarity in SAR between these 6,14-bridged oripavines and the 14-cinnamoylamino series suggests a similar mode of interaction with the micro opioid receptor.

Topics: Analgesics; Animals; Binding, Competitive; CHO Cells; Cinnamates; Cricetinae; Cricetulus; Humans; Ligands; Mice; Molecular Conformation; Narcotic Antagonists; Radioligand Assay; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Structure-Activity Relationship; Thebaine

This report presents the recommendations of a WHO Expert Committee responsible for reviewing information on dependence-producing drugs to assess the need for their international control. The first part of the report contains a summary of the Committee's evaluations of seven substances (dronabinol, oripavine, buprenorphine, butorphanol, ketamine, khat and zopiclone). The report also discusses the substances that were pre-reviewed (gamma-hydroxybutyric acid and tramadol) and recommended gamma-hydroxybutyric acid for critical review at a future meeting. Two substances (gamma-butyrolactone and 1,4-butanediol) were identified for future pre-review). The second part of the report discusses the guidelines for the WHO review of dependence-producing psychoactive substances for international control. It includes sections on amending the current guidelines, interpretation of specific aspects of the guidelines and access to information necessary for the evaluation of substances. The final section considers other matters including activities of the EMCCDA, the use of pharmacovigilance data, promotion of education and information on the appropriate use of psychoactive drugs and the impact of international control on medical availability of substances.

Topics: 4-Butyrolactone; Advisory Committees; Azabicyclo Compounds; Buprenorphine; Butorphanol; Catha; Dronabinol; Drug and Narcotic Control; Drug Evaluation; Health Services Accessibility; Humans; Hydroxybutyrates; Ketamine; Piperazines; Psychotropic Drugs; Substance-Related Disorders; Thebaine; Tramadol; World Health Organization

The opium poppy is a source of the pharmaceuticals codeine, morphine and their derived analgesics. Here we describe the initial characterization of the poppy mutant known as top1 (for 'thebaine oripavine poppy 1'), which accumulates the morphine and codeine precursors thebaine and oripavine and does not complete their biosynthesis into morphine and codeine. The original discovery of top1 stimulated a re-engineering of the opioid industry in the island state of Tasmania, which grows over 40% of the world's licit opiates, in order to produce thebaine and oripavine efficiently from morphine-free poppy crops to provide precursors for highly effective analgesics and for treatment of opioid addiction.

Topics: Analgesics, Opioid; Gene Expression Profiling; Gene Expression Regulation, Plant; Genes, Plant; Morphine; Mutation; Oligonucleotide Array Sequence Analysis; Papaver; Phenotype; Thebaine

A simple and robust capillary electrophoresis chemiluminescence detection system for the determination of morphine, oripavine and pseudomorphine is described, based upon the reaction of these analytes with acidic potassium permanganate in the presence of sodium polyphosphate. The reagent solution was contained in a quartz detection cell which also held both the capillary and the anode. The resultant chemiluminescence was monitored directly using a photomultiplier tube mounted flush against the base of the detection cell. To ensure that no migration of the permanganate anion occurred, the anode was placed at the detector end whilst the electroosmotic flow was reversed by the addition of hexadimethrine bromide (0.001% m/v) to the electrolyte. The three analytes were separated counter to the electroosmotic flow via their interaction with alpha-cyclodextrin. The methodology realised detection limits (3 x S/N) of 2.5 x 10(-7) M for both morphine and oripavine and 5 x 10(-7) M for pseudomorphine. The relative standard deviations of the migration times and the peak heights for the three analytes ranged from 0.6 up to 0.8% and from 1.5 up to 2.1%, respectively.

Topics: Electrophoresis, Capillary; Luminescent Measurements; Morphine; Morphine Derivatives; Narcotics; Thebaine

This study examines the possibility that oripavine opioid receptor agonists bind equally to both high and low affinity states of the mu-opioid receptor. Studies were performed in C6 cells expressing mu- or delta-opioid receptors; high and low agonist affinity states of the receptors were defined by the absence and presence, respectively of Na+ ions and the GTP analog Gpp(NH)p. At the mu-opioid receptor dihydroetorphine and etorphine were full agonists, buprenorphine had moderate efficacy while diprenorphine was an antagonist. At the delta-opioid receptor, dihydroetorphine, etorphine, and diprenorphine had moderate efficacy while buprenorphine was an antagonist. The binding affinities of the oripavines at the mu-opioid receptor decreased only one to 2-fold in the presence of NaCl and Gpp(NH)p. In contrast, decreases in oripavine affinity at the delta-opioid receptor correlated with delta-opioid receptor efficacy. The ability of oripavine agonists to bind with high affinity to the low agonist affinity state of the nu-opioid receptor may explain the high potencies of these compounds in vivo.

Topics: Analgesics, Opioid; Animals; Benzamides; Binding, Competitive; Buprenorphine; Cloning, Molecular; Diprenorphine; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Etorphine; Fentanyl; Guanosine 5'-O-(3-Thiotriphosphate); Morphine; Naloxone; Piperazines; Radioligand Assay; Rats; Receptors, Opioid, delta; Receptors, Opioid, mu; Sulfur Radioisotopes; Thebaine; Tritium; Tumor Cells, Cultured

The present study was undertaken to compare the neurotoxic effects of three etorphine-like opiates (etorphine, dihydroetorphine, and another derivative of oripavine) and heroin with their ability to activate opiate receptors in human neuroblastoma cell line SK-N-SH as well as in two other neuronal cell lines. Neurotoxicity was measured by using [3H]-thymidine incorporation analysis, cell viability measurement and Cytosensor microphysiometry. It was found that, in spite of the very similar molecular structures of these opiates, they displayed significant differences in cytotoxicity, with etorphine and another derivative of oripavine possessing high potency but dihydroetorphine and heroin little effect. However, neurotoxic potency of the opiates was not directly correlated to their ability to activate opioid receptors, as determined by [35S]-guanylyl-5'-O-(gamma-tho)-triphosphate binding assay. These findings provide clear evidence of differential neurotoxicity of etorphine-like opiates, and suggest that the neurotoxicity is not closely related to the molecular configuration required as opioid receptor agonist but is probably associated with the presence of a double bond in the structure.

Topics: Animals; Cell Survival; Etorphine; Guanosine 5'-O-(3-Thiotriphosphate); Heroin; Humans; Narcotics; Neuroblastoma; Neurotoxins; PC12 Cells; Rats; Receptors, Opioid; Structure-Activity Relationship; Thebaine; Tumor Cells, Cultured

1. Codeine O-demethylation to morphine is mediated by cytochrome P450 IID1 (rat), or P450 IID6 (man), and exhibits genetic polymorphism. Thebaine is a precursor in the formation of endogenous morphine and codeine in man, being O-demethylated to oripavine. 2. The objective of the present study was to ascertain whether the O-demethylation of thebaine to oripavine was mediated by cytochrome P450 IID1 in rat liver microsomes. 3. Thebaine O-demethylation showed strain differences in female Sprague-Dawley (SD) and female Dark-Agouti (DA) rats, which serve as a model for the human debrisoquine/sparteine metabolism phenotypes. 4. The total intrinsic clearance of thebaine to oripavine was high (19.7 ml/h per mg protein) in SD rats, indicating that oripavine is a major metabolite of thebaine. A 3-fold lower intrinsic clearance was observed in DA rats (6.7 ml/h per mg protein). 5. Thebaine O-demethylation was inhibited by quinine and known substrates of cytochrome P450 IID1/P450 IID6, supporting the major involvement of cytochrome P450 IID1 in oripavine formation in rats.

Topics: Animals; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Female; Kinetics; Methylation; Microsomes, Liver; Mixed Function Oxygenases; Rats; Rats, Inbred Strains; Species Specificity; Thebaine

Thebaine, an intermediate of morphine biosynthesis in the poppy plant, Papaver somniferum, was transformed to oripavine, codeine, and morphine by rat liver, kidney, and brain microsomes in the presence of an NADPH-generating system. The formation of morphine, codeine, and oripavine was identified by a specific RIA, HPLC, and GCMS. Thebaine also gave rise to four other compounds, which for the moment are unidentified. NADH dramatically increased the formation of both codeine and morphine when used together with an NADPH-generating system, especially in liver microsomes. NADPH is essential in the formation of oripavine from thebaine and morphine from codeine, while NADH is critical in the conversion of thebaine to codeine and from oripavine to morphine. Carbon monoxide or SKF 525A inhibited the conversion, indicating a role of cytochrome P-450. These results provide evidence for the enzymatic in vitro conversion by mammalian tissues of thebaine to morphine. The pathway is similar to that which exists in plants.

Topics: Animals; Biotransformation; Brain; Carbon Monoxide; Codeine; Kidney; Male; Microsomes; Microsomes, Liver; Morphine; NAD; NADP; Pyridines; Rats; Rats, Inbred Strains; Thebaine

The relative in vivo receptor affinities of three oripavine drugs given subcutaneously were determined at the mu, delta and kappa type of opiate binding sites in rat brain. The oripavines include the agonist etorphine, the antagonist diprenorphine and the mixed agonist-antagonist buprenorphine. With the use of mu, delta and kappa specific labeling conditions in brain homogenates immediately after sacrifice (ex vivo labeling), the method relies on the assay of those receptor sites that remain unbound in vivo. Because of the slow receptor binding kinetics of the oripavines, little or no dissociation of the in vivo ligand occurs during the ex vivo labeling period. All three drugs displayed lower affinity in vivo at the delta sites relative to mu sites, whereas the kappa affinities were highly variable. Etorphine displayed considerable mu selectivity, while burpenorphine's affinity at the mu and kappa sites was similar. The apparent in vivo binding affinities obtained from the ex vivo labeling approach are compatible with previous results where tracers were applied in vivo. The dramatic differences of the in vivo and in vitro opiate receptor binding properties of the oripavines demonstrate the need for in vivo receptor binding parameters in the analysis of the function of individual receptor types.

Topics: Animals; Brain; Buprenorphine; Diprenorphine; Etorphine; Kinetics; Male; Morphinans; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Thebaine

Topics: Morphine; Papaver; Plants, Medicinal; Thebaine

Buprenorphine (I), a member of the 6,14-endo-ethanotetrahydrooripavine series of analgesics, undergoes an acid-catalyzed rearrangement reaction when exposed to acid and heat. The product was shown by 1H-NMR and GC-MS to have undergone overall elimination of a molecule of methanol with concurrent formation of a tetrahydrofuran ring at C(6)-C(7) of I. Short-term stability studies across a wide range of pH and temperature conditions indicate that I is stable in aqueous solution at pH greater than 3 for 24 h at 36-38 degrees C. Under the more extreme conditions of the autoclave, significant loss of I occurred. Long-term stability studies (10 weeks) of I in aqueous solution (pH 1 and pH 5) at 0-4 degrees C and 26-28 degrees C indicate only minor conversion (4%) to the rearrangement product. Eight other 6,14-endo-ethanotetrahydrooripavine derivatives were subjected to extremes of acid (pH 0) and temperature (autoclave) to determine if similar rearrangement reactions occur. GC-MS indicated that hydrolysis products were produced whose spectra were consistent with the proposed rearrangement structures.

Topics: Analgesics; Buprenorphine; Catalysis; Drug Stability; Hydrogen-Ion Concentration; Hydrolysis; Morphinans; Thebaine

The analgesic activity of oripavine and phi-dihydrothebaine (5, 6, 8, 14-tetrahydro-4-hydroxy-3, 6-dimethoxy-17-methylmorphinan) has been studied in the mouse and rat with the hot-plate technique after s.c. drug administration. Peak analgesic effects in the mouse and rat were observed 20 min following drug administration, and the effect lasted about 40 to 60 min. Median analgesic (AD50) and lethal (LD50) doses and 95% confidence limits are presented. Oripavine and phi-dihydrothebaine appear to have analgesic potency of the same order as morphine in these species but have low therapeutic indexes because of severe toxicity. Toxic signs of oripavine and phi-dihydrothebaine in both species were clonic-tonic convulsions followed by death. The toxicity of oripavine, phi-dihydrothebaine and morphine in the mouse did not appear to be antagonized by pretreatment with 1 mg/kg of naloxone given 10 min prior to the test drug. toxicity does not appear to be mediated at the opiate receptor; however, oripavine did show some cross tolerance with morphine, but did not appear to suppress morphine abstinence in the mouse and rat.

Topics: Analgesics, Opioid; Animals; Drug Tolerance; Lethal Dose 50; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Pain; Rats; Rats, Inbred Strains; Thebaine

The 6-demethoxy analogue of thebaine has been easily prepared from codeine via isocodeine and its sulfenate ester. This diene, 7, readily undergoes reaction with vinyl ketones to afford Diels-Alder adducts of the 6,14-ethenomorphinan type. Further reactions afford the epimeric 19(R)- and 19(S)-butyl-6-demethoxy-7 alpha-orvinols (16). Pharmacological testing shows the R diastereomer to be highly analgesic and the s diastereomer to be a much less potent agonist, with similar potencies and relationships as found in the corresponding oripavine series. Thus, any hydrogen bonding between the 6-methoxyl group and the tertiary alcohol can be eliminated as contributory to either the activity of, or difference between the epimeric orvinols.

Topics: Analgesics; Animals; Chemical Phenomena; Chemistry; Dose-Response Relationship, Drug; Morphinans; Rats; Reaction Time; Thebaine; Time Factors

Topics: Analgesics; Benzomorphans; Cyclohexanes; Humans; Kinetics; Morphinans; Morphine Derivatives; Piperidines; Propylamines; Thebaine

Topics: Alkaloids; Molecular Structure; Papaver; Papaverine; Plants, Medicinal; Thebaine

A general synthesis of variously substituted 2,6-methano-3-benzazocine-11-propanols is described. Nine N-CH3 derivatives and their corresponding N-cyclopropylmethyl counterparts were prepared and studied in the mouse acetylcholine induced writhing and rat phenazocine antagonism tests. The results are compared with literature information on the bridged oripavine methanols. It is concluded that the synthetic analogues have a different structure-activity profile, in general being weak agonists but potent antagonists.

Topics: Acetylcholine; Analgesics, Opioid; Animals; Azocines; Mice; Molecular Conformation; Narcotic Antagonists; Phenazocine; Rats; Spasm; Structure-Activity Relationship; Thebaine

A practical synthesis of thebaine and oripavine has been developed from codeine and morphine, respectively. Attempts to use a codeinone intermediate gave poor yields; however, methylation of the potassium salt of codeine to give codeine methyl ether followed by oxidation with gamma-MnO2 gave thebaine in 67% yield from codeine. Similarly, the potassium salt of the di-O-anion of morphine was selectively alkylated to give morphine 6-methyl ether (heterocodeine) in better than 90% yield. Hetercodeine was then acetylated and oxidized to oripavine 3-acetate which was hydrolyzed to give oripavine in 73% yield from morphine.

Topics: Codeine; Methods; Methylation; Morphine; Oxidation-Reduction; Thebaine

Topics: Animals; Animals, Wild; Artiodactyla; Hypnotics and Sedatives; Morphine; Scopolamine; Thebaine; Tranquilizing Agents