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  1. Article ; Online: Recent Advances in the Chemistry of Oripavine and Its Derivatives

    Sandor Hosztafi

    Advances in Bioscience and Biotechnology, Vol 05, Iss 08, Pp 704-

    2014  Volume 717

    Abstract: Oripavine is the major alkaloid of Papaver orientale . It is an important intermediate in the biosynthesis of morphine alkaloids. Recently, new Papaver somniferum strains have been developed which accumulate thebaine and oripavine, but not morphine and ... ...

    Abstract Oripavine is the major alkaloid of Papaver orientale . It is an important intermediate in the biosynthesis of morphine alkaloids. Recently, new Papaver somniferum strains have been developed which accumulate thebaine and oripavine, but not morphine and codeine. Therefore, the chemistry of oripavine has been studied intensively to synthesize opioid pharmaceuticals such as oxymorphone, naloxone and buprenorphine.
    Keywords Papaver orientale ; Papaver somniferum ; Oripavine ; Thebaine ; Top1 Poppy ; Biology (General) ; QH301-705.5 ; Science ; Q
    Language English
    Publishing date 2014-07-01T00:00:00Z
    Publisher Scientific Research Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

    János Marton / Anikó Fekete / Paul Cumming / Sándor Hosztafi / Pál Mikecz / Gjermund Henriksen

    Molecules, Vol 27, Iss 2863, p

    2022  Volume 2863

    Abstract: 6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid ... ...

    Abstract 6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20 R -etorphine and 20 R -dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels–Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors.
    Keywords morphine alkaloids ; opioid receptors ; morphinan-6,8-dienes ; Diels–Alder reaction ; Grignard addition ; O -demethylation ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest

    Prof. Károly Mazák / Prof. Béla Noszál / Sándor Hosztafi

    ChemistryOpen, Vol 8, Iss 7, Pp 879-

    2019  Volume 887

    Abstract: Abstract This review focuses on recent developments in the physicochemical profiling of morphine and other opioids. The acid‐base properties and lipophilicity of these compounds is discussed at the microscopic, species‐specific level. Examples are ... ...

    Abstract Abstract This review focuses on recent developments in the physicochemical profiling of morphine and other opioids. The acid‐base properties and lipophilicity of these compounds is discussed at the microscopic, species‐specific level. Examples are provided where this type of information can reveal the mechanism of pharmacokinetic processes at the submolecular level. The role of lipophilicity in quantitative structure–activity relationship (QSAR) studies of opioids is reviewed. The physicochemical properties and pharmacology of the main metabolites of morphine are also discussed. Recent studies indicate that the active metabolite morphine‐6‐glucuronide (M6G) can contribute to the analgesic activity of systemically administered morphine. The unexpectedly high lipophilicity of M6G partly accounts for its analgesic activity. When administered parenterally, another suspected minor metabolite, morphine‐6‐sulfate (M6S) has superior antinociceptive effects to those of morphine. However, because sulfate esters of morphine derivatives cannot cross the blood‐brain barrier these esters may be good candidates to develop peripheral analgesic drugs.
    Keywords basicity ; glucuronide conjugates ; lipophilicity ; physicochemical profiling ; opioids ; Chemistry ; QD1-999
    Subject code 540
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher Wiley-VCH
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Synthesis of Potential Haptens with Morphine Skeleton and Determination of Protonation Constants

    István Köteles / Károly Mazák / Gergő Tóth / Boglárka Tűz / Sándor Hosztafi

    Molecules, Vol 25, Iss 4009, p

    2020  Volume 4009

    Abstract: Vaccination could be a promising alternative warfare against drug addiction and abuse. For this purpose, so-called haptens can be used. These molecules alone do not induce the activation of the immune system, this occurs only when they are attached to an ...

    Abstract Vaccination could be a promising alternative warfare against drug addiction and abuse. For this purpose, so-called haptens can be used. These molecules alone do not induce the activation of the immune system, this occurs only when they are attached to an immunogenic carrier protein. Hence obtaining a free amino or carboxylic group during the structural transformation is an important part of the synthesis. Namely, these groups can be used to form the requisite peptide bond between the hapten and the carrier protein. Focusing on this basic principle, six nor-morphine compounds were treated with ethyl acrylate and ethyl bromoacetate, while the prepared esters were hydrolyzed to obtain the N -carboxymethyl- and N -carboxyethyl-normorphine derivatives which are considered as potential haptens. The next step was the coupling phase with glycine ethyl ester, but the reactions did not work or the work-up process was not accomplishable. As an alternative route, the normorphine-compounds were N -alkylated with N -(chloroacetyl)glycine ethyl ester. These products were hydrolyzed in alkaline media and after the work-up process all of the derivatives contained the free carboxylic group of the glycine side chain. The acid-base properties of these molecules are characterized in detail. In the N -carboxyalkyl derivatives, the basicity of the amino and phenolate site is within an order of magnitude. In the glycine derivatives the basicity of the amino group is significantly decreased compared to the parent compounds (i.e., morphine, oxymorphone) because of the electron withdrawing amide group. The protonation state of the carboxylate group significantly influences the basicity of the amino group. All of the glycine ester and the glycine carboxylic acid derivatives are currently under biological tests.
    Keywords hapten ; vaccine ; immunotherapy ; N -demethylation ; nor-compounds ; morphine skeleton ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: A cost-effective synthesis of enantiopure ovothiol A from L-histidine, its natural precursor

    Arash Mirzahosseini / Sándor Hosztafi / Tóth Gergő / Béla Noszál

    ARKIVOC, Vol 2014, Iss 6, Pp 1-

    2014  Volume 9

    Keywords Organic chemistry ; QD241-441
    Language English
    Publishing date 2014-09-01T00:00:00Z
    Publisher Arkat USA, Inc.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: N-Phenethyl Substitution in 14-Methoxy-N-methylmorphinan-6-ones Turns Selective µ Opioid Receptor Ligands into Dual µ/δ Opioid Receptor Agonists

    Maria Dumitrascuta / Marcel Bermudez / Tanila Ben Haddou / Elena Guerrieri / Lea Schläfer / Andreas Ritsch / Sandor Hosztafi / Aquilino Lantero / Christoph Kreutz / Dominique Massotte / Helmut Schmidhammer / Gerhard Wolber / Mariana Spetea

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 12

    Abstract: Abstract Morphine and structurally-derived compounds are µ opioid receptor (µOR) agonists, and the most effective analgesic drugs. However, their usefulness is limited by serious side effects, including dependence and abuse potential. The N-substituent ... ...

    Abstract Abstract Morphine and structurally-derived compounds are µ opioid receptor (µOR) agonists, and the most effective analgesic drugs. However, their usefulness is limited by serious side effects, including dependence and abuse potential. The N-substituent in morphinans plays an important role in opioid activities in vitro and in vivo. This study presents the synthesis and pharmacological evaluation of new N-phenethyl substituted 14-O-methylmorphinan-6-ones. Whereas substitution of the N-methyl substituent in morphine (1) and oxymorphone (2) by an N-phenethyl group enhances binding affinity, selectivity and agonist potency at the µOR of 1a and 2a, the N-phenethyl substitution in 14-methoxy-N-methylmorphinan-6-ones (3 and 4) converts selective µOR ligands into dual µ/δOR agonists (3a and 4a). Contrary to N-methylmorphinans 1–4, the N-phenethyl substituted morphinans 1a–4a produce effective and potent antinociception without motor impairment in mice. Using docking and molecular dynamics simulations with the µOR, we establish that N-methylmorphinans 1–4 and their N-phenethyl counterparts 1a–4a share several essential receptor-ligand interactions, but also interaction pattern differences related to specific structural features, thus providing a structural basis for their pharmacological profiles. The emerged structure-activity relationships in this class of morphinans provide important information for tuning in vitro and in vivo opioid activities towards discovery of effective and safer analgesics.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2020-03-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6- O -sulfate and Codeine-6- O -sulfate

    Ferenc Zádor / Amir Mohammadzadeh / Mihály Balogh / Zoltán S. Zádori / Kornél Király / Szilvia Barsi / Anna Rita Galambos / Szilvia B. László / Barbara Hutka / András Váradi / Sándor Hosztafi / Pál Riba / Sándor Benyhe / Susanna Fürst / Mahmoud Al-Khrasani

    Molecules, Vol 25, Iss 6, p

    2020  Volume 1370

    Abstract: The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6- O -sulfate (14-OMeC6SU), compared to the reference compounds codeine-6- O - ... ...

    Abstract The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6- O -sulfate (14-OMeC6SU), compared to the reference compounds codeine-6- O -sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [ 35 S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund’s Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.
    Keywords peripheral antinociception ; 14-methoxycodeine-6- o -sulfate ; codeine-6- o -sulfate ; Organic chemistry ; QD241-441
    Subject code 570
    Language English
    Publishing date 2020-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Pharmacological investigations of N-substituent variation in morphine and oxymorphone

    Tanila Ben Haddou / Szabolcs Béni / Sándor Hosztafi / Davide Malfacini / Girolamo Calo / Helmut Schmidhammer / Mariana Spetea

    PLoS ONE, Vol 9, Iss 6, p e

    opioid receptor binding, signaling and antinociceptive activity.

    2014  Volume 99231

    Abstract: Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the µ opioid ... ...

    Abstract Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the µ opioid peptide (MOP) receptor, a G protein-coupled receptor. Position 17 in morphine has been one of the most manipulated sites on the scaffold and intensive research has focused on replacements of the 17-methyl group with other substituents. Structural variations at the N-17 of the morphinan skeleton led to a diversity of molecules appraised as valuable and potential therapeutics and important research probes. Discovery of therapeutically useful morphine-like drugs has also targeted the C-6 hydroxyl group, with oxymorphone as one of the clinically relevant opioid analgesics, where a carbonyl instead of a hydroxyl group is present at position 6. Herein, we describe the effect of N-substituent variation in morphine and oxymorphone on in vitro and in vivo biological properties and the emerging structure-activity relationships. We show that the presence of a N-phenethyl group in position 17 is highly favorable in terms of improved affinity and selectivity at the MOP receptor, potent agonism and antinociceptive efficacy. The N-phenethyl derivatives of morphine and oxymorphone were very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, they were highly effective against acute thermal nociception in mice with marked increased antinociceptive potency compared to the lead molecules. It was also demonstrated that a carbonyl group at position 6 is preferable to a hydroxyl function in these N-phenethyl derivatives, enhancing MOP receptor affinity and agonist potency in vitro and in vivo. These results expand the understanding of the impact of different moieties at the morphinan nitrogen on ligand-receptor interaction, molecular mode of action and signaling, and may be instrumental to the development of new opioid therapeutics.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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