DOCSLIB.ORG

Proteinogenic Brain Impermeant Amino Acid, Isovaline

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

ANTIALLODYNIA AND SURGICAL IMMOBILITY PRODUCED BY THE NON- PROTEINOGENIC BRAIN IMPERMEANT AMINO ACID, ISOVALINE by Ryan Arthur Whitehead B.Sc. (Honours), The University of British Columbia, 2007 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pharmacology & Therapeutics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2013 ©Ryan Arthur Whitehead, 2013 Abstract This thesis describes research stemming from investigation of the novel nonproteinogenic amino acid, isovaline. The first chapter is a background for the field of study. The second chapter investigates peripheral GABAB receptor-mediated mechanisms of action of isovaline, ɤ-aminobutyric acid (GABA), and baclofen. The third chapter details experimental evidence demonstrating that a combination of central hypnosis and peripheral analgesia produces general anesthesia. The fourth chapter describes the development and evaluation of a novel model of human trigeminal allodynia, a feature of intractable and severe pain in trigeminal neuralgia. The mechanism of action of isovaline, as for GABA and baclofen, was found involve peripheral GABAB receptors, revealed through attenuation of peripheral prostaglandin E2 (PGE2)-induced allodynia. This mechanism was tested by reversal of allodynia by the GABAB antagonist CGP52432 and potentiation of allodynia by the GABAB positive modulator CGP7930. Immunohistochemical staining showed confluence of GABAB1 and GABAB2 subunits on free nerve endings and keratinocytes. Peripherally administered isovaline and GABA produced analgesia but no CNS depression, whereas baclofen produced analgesia accompanied by pronounced sedation and hypothermia. In a forced exercise model of osteoarthritic dysfunction isovaline restored joint operability lost presumably due to knee pain. Next, we hypothesized that co-administration of a peripherally restricted analgesic with a central hypnotic (isovaline co-administered with propofol) would produce general anesthesia in mice. We first demonstrated that isovaline and fentanyl produced surgical analgesia without appreciable sedation. Propofol alone produced hypnosis without analgesia or surgical anesthesia. ii When administered with hypnotic doses of propofol, coadministration of isovaline resulted in general anesthesia. Under fixed ratio hypnotic and analgesic dose ratios, propofol-isovaline anesthesia had a markedly higher therapeutic index than propofol-fentanyl. When co- administered with a fixed hypnotic dose of propofol, isovaline in contrast to fentanyl did not have a maximum tolerated dose (MTD). Next we describe an intracisternal strychnine mouse model of human trigeminal neuropathic pain is described. The model reflects the efficacy of clinical drug treatments as morphine administered intraperitoneally was not effective, but intracisternally injected carbamazepine epoxide provided pain relief. Isovaline applied near the spinal trigeminal nucleus was effective in this model, validating its utility in detecting efficacy of novel analgesics. iii Preface My contributions to chapter two were undertaking the in vivo experiments, and the experimental design, analysis and the writing associated with it, and undertook the journal submission processes under supervision of Drs. Bernard MacLeod and Ernest Puil in the Hugill Centre for Anesthesia and Analgesia. The development of the manuscript was also subjected to significant collaborative advice from Drs. Schwarz and Ries. A version of chapter two has been published: Whitehead RA, Puil E, Ries CR, Schwarz SK, Wall RA, Cooke JE, Putrenko I, Sallam NA, MacLeod BA. GABA(B) receptor-mediated selective peripheral analgesia by the non- proteingogenic amino acid, isovaline. Neuroscience 213: 154-60, 2012. My contribution to chapter three was in the design, conducting, and analysing of experiments and writing associated with it. All experiments were undertaken in the Hugill Centre for Anesthesia and Analgesia. I wrote the manuscript and undertook the journal submission process, under supervision of Drs. Bernard MacLeod, Ernest Puil and Stephan Schwarz co-wrote the manuscript with me. A version of chapter is in preparation for peer-reviewed publication: Whitehead, R.A., Puil, E., Ries, C.R., Schwarz S.K., Fung, T., MacLeod, B.A. Isovaline co- administered with propofol produces general anesthesia in mice. In preparation for submission, 2013. My contribution to the fourth chapter was in the design, validation of experimental procedures, and analysis of experiments and writing of the manuscript. All experiments were undertaken in the Hugill Centre for Anesthesia and Analgesia. Drs. Bernard MacLeod, Ernest Puil and Stephan iv Schwarz co-wrote the manuscript with me. I also contributed, through review of experimental data, blind re-evaluation of data transformed to a new non-parametric allodynia score system, re- analysis of data including new statistical approaches. I wrote the manuscript in collaboration with Drs. MacLeod, Puil and Schwarz and undertook the journal submission process. A version of chapter four has been pubished: Lee IO, Whitehead RA, Ries CR, Schwarz SK, Puil E, MacLeod BA. Evaluation of a novel mouse model of intracisternal strychnine-induced trigeminal allodynia. Can J Anaesth [Epub ahead of print], 2013. v Table of Contents Abstract .......................................................................................................................................... ii Preface ........................................................................................................................................... iv Table of Contents ......................................................................................................................... vi List of Tables ................................................................................................................................ ix List of Figures .................................................................................................................................x List of Abbreviations ................................................................................................................... xi Acknowledgements ..................................................................................................................... xii Dedication ................................................................................................................................... xiii Chapter 1: General Introduction .................................................................................................1 1.1 Scope of thesis ................................................................................................................ 2 1.2 Background ..................................................................................................................... 5 1.2.1 Definitions of pain, allodynia and hyperalgesia ......................................................... 5 1.3 Ascending pain pathways ............................................................................................... 7 1.3.1 Neospinothalamic tract ............................................................................................... 9 1.3.1 Paleospinothalamic tract ........................................................................................... 10 1.3.1 Archispinothalamic tract ........................................................................................... 11 1.4 Translational pain testing preparations in vivo ............................................................. 11 1.4.1 Tail-flick assay .......................................................................................................... 12 1.4.2 Acute chemical pain .................................................................................................. 13 1.4.3 Chronic pain .............................................................................................................. 15 1.4.4 Osteoarthritis ............................................................................................................ 16 1.4.5 Models of allodynia .................................................................................................. 18 1.4.6 Tourniquet intravenous regional analgesia ............................................................... 19 1.5 Analgesics, inhibitory amino acids and their receptors ................................................ 21 1.5.1 Non-steroidal anti-inflammatory drugs..................................................................... 22 1.5.2 Opioids ...................................................................................................................... 23 1.5.3 Gabapentinoids ......................................................................................................... 24 1.5.1 Glycine ...................................................................................................................... 26 1.5.2 γ-aminobutyric acid (GABA) ................................................................................... 28 1.5.3 GABAA receptors ...................................................................................................... 28 1.5.3 GABAB receptors ...................................................................................................... 29 1.5.3 Isovaline ...................................................................................................................
Recommended publications
  • Determining the Role of Gabaergic Signaling in The

    Determining the Role of Gabaergic Signaling in The

    DETERMINING THE ROLE OF GABAERGIC SIGNALING IN THE CRANIOFACIAL DEVELOPMENT OF LARVAL ZEBRAFISH by LINDSEY L. BEEBE (Under the Direction of James D. Lauderdale) ABSTRACT Although best known as an inhibitory neurotransmitter, intriguing evidence has implicated GABA as a key signaling molecule in craniofacial development in mammals. Glutamate is converted to GABA by an enzyme called glutamic acid decarboxylase (GAD), which exists in two isoforms, GAD67 and GAD65. The GAD1 and GAD2 genes encode these isoforms, respectively. A decrease in GAD activity in the human brain is often associated with epilepsy, schizophrenia and related neurological disorders. In mice and humans, mutations in gad1, but not gad2, result in defects in palate development, and mutations in the Gabrb3 gene, which encodes the β3 subunit of the GABAA receptor, exhibit a comparable phenotype to gad1 mutations. These results suggest that GABA signaling, through the GABAA receptor, can play an important and conserved role in craniofacial development. However, the mechanism of this process is not known and cannot be easily investigated in a mammalian system. In this work, translation-blocking morpholinos against the GAD genes were used to alter expression within the larval zebrafish. While gad2 morphants looked phenotypically normal, gad1 morphant animals exhibited altered cranial structures at 1 and 7 dpf. Yet, both gad1 and gad2 morphants exhibited spontaneous seizure-like neural activity. Through the use of photoactivatable caged-morpholinos, the craniofacial deformities could be bypassed when photolysis was carried out at 24 hpf. Electrophysiological recordings showed that while dark-raised CyHQ-gad1 morphant animals looked phenotypically comparable to wild-type animals, they exhibited abnormal, seizure-like neural activity.
  • Neurotransmitters-Drugs Andbrain Function.Pdf

    Neurotransmitters-Drugs Andbrain Function.Pdf

    Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Edited by R. A. Webster Department of Pharmacology, University College London, UK JOHN WILEY & SONS, LTD Chichester Á New York Á Weinheim Á Brisbane Á Singapore Á Toronto Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Copyright # 2001 by John Wiley & Sons Ltd. Bans Lane, Chichester, West Sussex PO19 1UD, UK National 01243 779777 International ++44) 1243 779777 e-mail +for orders and customer service enquiries): [email protected] Visit our Home Page on: http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1P0LP,UK, without the permission in writing of the publisher. Other Wiley Editorial Oces John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA WILEY-VCH Verlag GmbH, Pappelallee 3, D-69469 Weinheim, Germany John Wiley & Sons Australia, Ltd.
  • GABA Receptors

    GABA Receptors

    D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43.
  • Cell Surface Mobility of GABAB Receptors Saad Bin

    Cell Surface Mobility of GABAB Receptors Saad Bin

    Cell surface mobility of GABAB receptors Saad Bin Hannan September 2011 A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy of the University College London Department of Neuroscience, Physiology, and Pharmacology University College London Gower Street London WC1E 6BT UK Declaration ii ‘I, Saad Hannan confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.' ____________________ Saad Hannan September 2011 To Ammu, Abbu, Polu Abstract ivi Abstract Type-B γ-aminobutyric acid receptors (GABABRs) are important for mediating slow inhibition in the central nervous system and the kinetics of their internalisation and lateral mobility will be a major determinant of their signalling efficacy. Functional GABABRs require R1 and R2 subunit co-assembly, but how heterodimerisation affects the trafficking kinetics of GABABRs is unknown. Here, an α- bungarotoxin binding site (BBS) was inserted into the N-terminus of R2 to monitor receptor mobility in live cells. GABABRs are internalised via clathrin- and dynamin- dependent pathways and recruited to endosomes. By mutating the BBS, a new technique was developed to differentially track R1a and R2 simultaneously, revealing the subunits internalise as heteromers and that R2 dominantly-affects constitutive internalisation of GABABRs. Notably, the internalisation profile of R1aR2 heteromers, but not R1a homomers devoid of their ER retention motif (R1ASA), is similar to R2 homomers in heterologous systems. The internalisation of R1aASA was slowed to that of R2 by mutating a di-leucine motif in the R1 C-terminus, indicating a new role for heterodimerisation, whereby R2 subunits slow the internalization of surface GABABRs.
  • Isovaline Monohydrate

    Isovaline Monohydrate

    organic compounds Acta Crystallographica Section E Structure Reports Online ISSN 1600-5368 Isovaline monohydrate Ray J. Butcher,a* Greg Brewer,b Aaron S. Burtonc and Experimental d Jason P. Dworkin Crystal data ˚ 3 C5H11NO2ÁH2O V = 736.10 (12) A aDepartment of Chemistry, Howard University, 525 College Street NW, Washington, Mr = 135.16 Z =4 DC 20059, USA, bDepartment of Chemistry, Catholic University of America, Orthorhombic, P212121 Cu K radiation Washington, DC 20064, USA, cNASA Johnson Space Center, Astromaterial and a = 5.9089 (5) A˚ = 0.84 mmÀ1 Exploration Science Directorate, Houston, TX 77058, USA, and dSolar System b = 10.4444 (10) A˚ T = 123 K Exploration Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771, c = 11.9274 (11) A˚ 0.48 Â 0.08 Â 0.06 mm USA Correspondence e-mail: [email protected] Data collection Agilent Xcalibur (Ruby, Gemini) 1662 measured reflections Received 23 October 2013; accepted 20 November 2013 diffractometer 1204 independent reflections Absorption correction: multi-scan 1072 reflections with I >2(I) (CrysAlis PRO; Agilent, 2012) Rint = 0.072 ˚ Key indicators: single-crystal X-ray study; T = 123 K; mean (C–C) = 0.005 A; Tmin = 0.383, Tmax = 1.000 R factor = 0.056; wR factor = 0.162; data-to-parameter ratio = 13.2. Refinement R[F 2 >2(F 2)] = 0.056 H atoms treated by a mixture of The title compound, C5H11NO2ÁH2O, is an isomer of the - wR(F 2) = 0.162 independent and constrained amino acid valine that crystallizes from water in its zwitterion S = 1.11 refinement ˚ À3 form as a monohydrate.
  • Alma Mater Studiorum –– Università Di Bologna

    Alma Mater Studiorum –– Università Di Bologna

    Alma Mater Studiorum –– Università di Bologna DOTTORATO DI RICERCA IN Scienze Chimiche Ciclo XXIV Settore Concorsuale di afferenza: CHIM/06 Settore Scientifico disciplinare: CHIMICA ORGANICA TITOLO TESI Synthesis of Modified Amino Acids and Insertion in Peptides and Mimetics. Structural Aspects and Impact on Biological Activity. Presentata da: De Marco Rossella Coordinatore Dottorato Relatore Prof. Adriana Bigi Prof. Luca Gentilucci Esame finale anno 2012 1 Synthesis of Modified Amino Acids and Insertion in Peptides and Mimetics. Structural Aspects and Impact on Biological Activity. by Rossella De Marco 2012 2 To My Self 3 Table of Contents Cap 1. Chemical Modifications Designed to Improve Peptide Stability 1. Introduction 1.2. Enzymatic Degradation of Peptides 1.3. Structure Modifications to Improve Peptide Stability 1.3.1.Pseudopeptides 1.3.2. Reduced Peptide Bonds 1.3.3. Azapeptides 1.3.4. Retro-Inverso Peptides 1.3.5. Peptoids 1.4. Incorporation of Non-Natural Amino Acids 1.4.1. D-Amino Acids 1.4.2. N-Alkylated Amino Acids 1.4.3. α-Substituted α-Amino-Acids 1.4.4. β-Substituted α-Amino Acids 1.4.5. Proline analogues 1.4.6. β-Amino-Acids 1.5. Cyclization 1.6. β-Turn-Mimetics 1.7. Conclusion References Chapter 2. Cyclopeptide Analogs for Generating New Molecular and 3D Diversity. 2. Introduction 2. 1. Matherial and Methods 2.2. General Methods. 2.3. General Procedure for Peptide Coupling 2.3.1. Boc group deprotection 2.3.2. Fmoc group deprotection 2.3.3. Cbz and benzyl group deprotection 2.3.4. General Procedure for Peptide Cyclization 2.4.
  • Metabolism of D1-Valine and D1-Isovaline in the Normal

    Metabolism of D1-Valine and D1-Isovaline in the Normal

    Ai ABSTRACT OF ThE THESIS OF ___________ for (Naine) (Degree) (Majer) Date Thesis presented__._-J-9LJ-____ THE T i tie - - 9 .PY. NO.MAL RAT- Abstract Approved: (kiajor Professor) Up to the present time no in±ormation is available as to the role of di-valine in metabolism except that it is an ind.ispensllJle amino acid. and must be su.pplied in the diet of' the animal if' growth and. life is to contlnu.e. Experimental techniques that lately have been applied. to the stu.ay of other amino acids might yield sorne inform- ation in this problem and assign to di-valine a definite role as a glycogenic or as a ketone-prod.u.cing compound. The ketolytic properties of di-valine have beem dem- onstrated by the decrease in level of acetonuria of' fasting rats fed di-valine when the ketonaria arises from endogen- oua stores. These ketolrt1c results have been further substantiated when fasting rats were fed. sodium butyrate to heighten the already existing acetonu.ria. This ketolytic effect should derive its origin from the formation of' liver glycogen. Liver glycogen studies were carried. out to test this hypothesis. Small but sign- ificant amounts of glycogen were founa after feeding dl- valine. Thus, affording further proof' that di-valine may be considered a weakly glycogenic amino acid. No glycogen was found after feeding di-isovaline. Absorption studies were made and the rates of absorp- tion of di-valine and di-isovaline were found to confirm to the values previously reported by Chase and Lewis.
  • FACULTY Dates Listed in Parentheses Indicate Year of Tenure-Track Appoint- Chiara D

    FACULTY Dates Listed in Parentheses Indicate Year of Tenure-Track Appoint- Chiara D

    FACULTY Dates listed in parentheses indicate year of tenure-track appoint- Chiara D. Bacigalupa (2007) ment to Sonoma State University. Associate Professor, Literacy, Elementary, and Early Education List as of September 26, 2014 B.A. 1987, University of California, Santa Cruz M.A. 1991, California State University, Northridge Judith E. Abbott (1991) Ph.D. 2005, University of Minnesota Professor, History B.A. 1970, University of Minnesota Christina N. Baker (2008) M.A. 1977, Ph.D. 1989, University of Connecticut Associate Professor, American Multicultural Studies B.A. 2000, University of California, Los Angeles Emily E. Acosta Lewis (2013) M.A. 2003, Ph.D. 2007, University of California, Irvine Assistant Professor, Communication Studies B.A. 2005, California State University, San Diego Jeffrey R. Baldwin (2009) M.A. 2008, Ph.D. 2012, University of Wisconsin-Madison Associate Professor, Geography and Global Studies B.A. 1979, M.A. 1998, Ph.D. 2003, University of Oregon Theresa Alfaro-Velcamp (2003) Professor, History Melinda C. Barnard (1990) B.A. 1989, California Polytechnic State University, San Luis Obispo Associate Vice President for Faculty Affairs, M.S. 1990, London School of Economics and Political Science and Chief Research Officer M.A. 1995, Ph.D. 2001, Georgetown University Professor, Communication Studies B.A. 1975, Ph.D. 1986, Stanford University Ruben Armiñana (1992) M.A. 1976, Harvard University President, Sonoma State University; Professor, Political Science A.A. 1966, Hill College Edward J. Beebout (2007) B.A. 1968, M.A. 1970, University of Texas at Austin Associate Professor, Communication Studies Ph.D. 1983, University of New Orleans B.A. 1981, Humboldt State University M.S.
  • (12) Patent Application Publication (10) Pub. No.: US 2005/0215521 A1 Lalji Et Al

    (12) Patent Application Publication (10) Pub. No.: US 2005/0215521 A1 Lalji Et Al

    US 20050215521A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0215521 A1 Lalji et al. (43) Pub. Date: Sep. 29, 2005 (54) MODAFINIL COMBINATION THERAPY FOR Publication Classification IMPROVING SLEEP QUALITY (51) Int. Cl.' .................. A61K 31/724; A61K 31/7008; (76) Inventors: Karim Lalji, Sudbury, MA (US); A61K 31/4164; A61K 31/195; Timothy J. Barberich, Concord, MA A61K 31/165 (US) (52) U.S. Cl. ............................ 514/58; 514/221; 514/389; 514/561; 514/557; 514/23; Correspondence Address: 514/618; 514/469 FOLEY HOAG, LLP PATENT GROUP, WORLD TRADE CENTER WEST (57) ABSTRACT 155 SEAPORT BLVD One aspect of the present invention relates to pharmaceutical BOSTON, MA 02110 (US) compositions comprising a compound that modulates the orexin System and a Sedative agent. In a preferred embodi (21) Appl. No.: 11/018,869 ment, the compound that modulates the orexin System is (22) Filed: Dec. 21, 2004 modafinil and the Sedative agent is eSZopiclone. The phar maceutical compositions of the invention are useful in the Related U.S. Application Data treatment of various sleep disorders. In addition, the present invention relates to a method of treating a patient Suffering (60) Provisional application No. 60/531,822, filed on Dec. from a sleep abnormality or insomnia comprising adminis 22, 2003. Provisional application No. 60/541,684, tering a therapeutically effective amount of a pharmaceutical filed on Feb. 4, 2004. composition of the invention. Patent Application Publication Sep. 29, 2005 Sheet 1 of 2 US 2005/0215521 A1 Figure 1 (RS)-Zopiclone D-Malic Acid Acetone Mixing/Heating Methanol Methanol-DCooling/Crystallizatio (S)-Zopiclone D-Malate See Methanol Filtration/Washing Mother Liquors/Washes -Ge IPC (S)-Zopiclone D-Malate Patent Application Publication Sep.
  • DAS Gabaerge SYSTEM

    DAS Gabaerge SYSTEM

    DIPLOMARBEIT Titel der Diplomarbeit „In vivo Untersuchung ausgewählter GABAA-Liganden auf das Verhalten von c57Bl/6N-Mäusen“ Verfasserin Sandra Maurer angestrebter akademischer Grad Magistra der Pharmazie (Mag.pharm.) Wien, 2013 Studienkennzahl lt. Studienblatt: A 449 Studienrichtung lt. Studienblatt: Diplomstudium Pharmazie Betreuer: Univ.-Prof. Dr. Steffen Hering DANKSAGUNG In erster Linie möchte ich mich bei Univ. Prof. Dr. Steffen Hering für die Ermöglichung dieser Diplomarbeit am Department für Pharmakologie und Toxikologie, sowie für die Bereitstellung dieses interessanten Themas bedanken. Ein Dankeschön gilt auch Mag. Dr. Sophia Khom für die hilfreichen und kompetenten Ratschläge zum Anfertigen dieser Arbeit. Herzlicher Dank gilt vor allem Mag. Juliane Hintersteiner, die mich bei allen praktischen Arbeiten begleitet, all meine Fragen geduldig beantwortet und mich mit großem Engagement unterstützt hat. Bedanken möchte ich mich weiters bei Mag. Barbara Strommer, die sich für mich eingesetzt hat, diesen Diplomarbeitsplatz zu bekommen. Auch bei meiner Familie möchte ich mich recht herzlich bedanken, dass sie mir das Studium der Pharmazie ermöglichten und mich auch in schwierigen Phasen des Studiums immer unterstützten. Besonderer Dank gilt auch meinem Freund Christoph, der immer an meiner Seite ist. INHALT A) ALLGEMEINER TEIL ................................................................................................................. 1 1. DAS GABAerge SYSTEM .....................................................................................................
  • Low Cerebral Exposure Cannot Hinder the Neuroprotective Effects of Panax Notoginsenosides

    Low Cerebral Exposure Cannot Hinder the Neuroprotective Effects of Panax Notoginsenosides

    DMD Fast Forward. Published on October 23, 2017 as DOI: 10.1124/dmd.117.078436 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 78436 Low cerebral exposure cannot hinder the neuroprotective effects of panax notoginsenosides Haofeng Li, Jingcheng Xiao, Xinuo Li, Huimin Chen, Dian Kang, Yuhao Shao, Boyu Shen, Zhangpei Zhu, Xiaoxi Yin, Lin Xie, Guangji Wang, Yan Liang Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China Downloaded from dmd.aspetjournals.org at ASPET Journals on September 25, 2021 1 DMD Fast Forward. Published on October 23, 2017 as DOI: 10.1124/dmd.117.078436 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 78436 Running Title Page Panax notoginsenosides exert neuroprotective effects Corresponding author: Yan Liang Co- corresponding author: Guangji Wang Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China. Tel: +86-25-83271060 Email: [email protected] [email protected] H.L. and J.X. contributed equally to this work. Downloaded from Number of text pages: 39 Number of figures: 8 Number of references: 59 dmd.aspetjournals.org Number of words in the Abstract: 217 Number of words in the Introduction: 929 Number of words in the Discussion: 1327 at ASPET Journals on September 25, 2021 Abbreviations:
  • Chimica Industriale Synthesis, Reactivity and Applications Of

    Chimica Industriale Synthesis, Reactivity and Applications Of

    Alma Mater Studiorum - Università di Bologna SCUOLA DI SCIENZE Dipartimento di Chimica Industriale “Toso Montanari” Corso di Laurea Magistrale in Chimica Industriale Classe LM-71 - Scienze e Tecnologie della Chimica Industriale Synthesis, reactivity and applications of 3,5- dimethyl-4-nitroisoxazole derivatives Tesi di laurea sperimentale CANDIDATO RELATORE Alberto Tampieri Chiar.mo Prof. Mauro Comes Franchini CORRELATORE Chiar.mo Prof. Mauro Adamo Sessione III ________________________________________________________________________________________________________________________ Anno Accademico 2014-2015 ________________________________________________________________________________________________________________________ Abstract 3,5-dimethyl-4-nitroisoxazole derivatives are useful synthetic intermediates as the isoxazole nucleus chemically behaves as an ester, but establish better-defined interactions with chiral catalysts and lability of its N-O aromatic bond can unveil other groups such as 1,3-dicarbonyl compounds or carboxylic acids. In the present work, these features are employed in a 3,5-dimethyl-4-nitroisoxazole based synthesis of the γ-amino acid pregabalin, a medication for the treatment of epilepsy and neuropatic pain, in which this moiety is fundamental for the enantioselective formation of a chiral center by interaction with doubly-quaternized cinchona phase-transfer catalysts, whose ability of asymmetric induction will be investigated. Influence of this group in cinchona-derivatives catalysed stereoselective addition