DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2012/0196835 A1 Olafield Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2012/0196835 A1 Olafield Et Al US 20120196835A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0196835 A1 Olafield et al. (43) Pub. Date: Aug. 2, 2012 (54) ENZYME INHIBITING COMPOUNDS AND A6II 3/663 (2006.01) METHODS A6II 3/94 (2006.01) CI2N 9/99 (2006.01) (76) Inventors: Eric Olafield, Champaign, IL (US); A6II 3L/225 (2006.01) Ke Wang, Urbana, IL (US); A6II 3/662 (2006.01) Weixue Wang, Urbana, IL (US); A6II 3/665 (2006.01) Yonghui Zhang, Urbana, IL (US) A6IP3L/04 (2006.01) A6IP33/00 (2006.01) (21) Appl. No.: 13/500,845 C07F 9/113 (2006.01) A 6LX 3L/95 (2006.01) (22) PCT Filed: Oct. 8, 2010 (52) U.S. Cl. ........... 514/89; 558/152; 514/106; 558/155; 514/108: 514/574: 514/563; 514/547: 514/119; (86). PCT No.: PCT/US 10/52049 514/99: 435/184 S371 (c)(1), (2), (4) Date: Apr. 6, 2012 (57) ABSTRACT The invention provides compounds, compositions, and meth Related U.S. Application Data ods for studying the Rohmer pathway and for treating bacte (60) Provisional application No. 61/249,929, filed on Oct. rial infections or parasitic infections. The parasitic infection 8, 2009. can be a protozoan infection, such as malaria. The compounds and compositions can also be used as antibiotics, for example, O O to kill bacteria or parasites, or to inhibit bacterial or parasite Publication Classification growth. The invention further provides inhibitors of iso (51) Int. Cl. prenoid biosynthesis enzymes, and methods of inhibiting the A6 IK3I/675 (2006.01) activity ofisoprenoid biosynthesis enzymes. The compounds A6 IK3I/665 (2006.01) can be, for example, alkynes or allenes that bind to a unique C07F 9/40 (2006.01) Fe of an Fe4S4 cluster of an isoprenoid biosynthesis enzyme. Patent Application Publication Aug. 2, 2012 Sheet 1 of 5 US 2012/0196835 A1 Acetylene Series: o O O O O O e1O YO1 13OH sulf- CPP.O1 OH BPH-1061 BPH-1077 BPH-1093 to ROH HO O OFOH n a 1 E. BPH-1085 O O O O HO, OH NN HO OH 21P-PS: nsuch a. of aoh BPH-1081 BPH-1082 Figure 1 Patent Application Publication Aug. 2, 2012 Sheet 2 of 5 US 2012/0196835 A1 Cationic Series: ROH ROH ROH n OH n OH n OH OH N OpHan O1. OpHan 1. NOHOpH2n BPH-2 BPH-21 BPH-9 g ROH g n OH n NOH n OH 1. 2P 1. 2P CH3 O1. OpHanI N OpHa' N OpHY BPH-2OO BPH-290 BPH-299 O MOH ROH OH OH NS-s PCO. O.N si-n- OH rich1 2P O1 OH an 2n OH OpH OpH BPH-297 BPH-650 BPH-639 NYo'no.'HO, SohOH N1 YO)'Ho YO1"YOHOH N 1 2N BPH-293 BPH-1026 BPH-1027 to. OH HoY as aOH 21 ro no- YOH 1. C N F Cro O OH (OluseSa O1' O1"E-OH OH BPH-1029 BPH-1060 BPH-1030 OH ROH i O O n OH n HoO1 NO- i.YOH HO al i Y OH r -N-N-P. r),2n H N OP BPH-1032 BPH-1028 BPH-272 Figure 2 Patent Application Publication Aug. 2, 2012 Sheet 3 of 5 US 2012/0196835 A1 Anionic, Thiol and Neutral Series: HOJiu-25 of SoFSoiOH HO, 1.N. toO'O' -OHOH HOJus N1O-O-SOHHo -OH O BPH-988 BPH-991 BPH-296 ROH ROH 's OH Hsn-n-2SoH OH sr- O?OH MeO Jusu:O1 O1"E-OH OH OH OH BPH-993 BPH-994 BPH-990 O O O O O O Mole-3-3HO OH OL>-CPP HO OH HO1\1\oHO Yo-SoHOH O BPH-989 BPH-432 BPH-1031 Figure 3 1.O O.8 O c. 0.6 S. 0.4 0.2 O.O O. 1 1O 1 OOO Inhibitor Concentration (uM) Figure 4 Patent Application Publication Aug. 2, 2012 Sheet 5 of 5 US 2012/0196835 A1 Figure 6 US 2012/0196835 A1 Aug. 2, 2012 ENZYME INHIBITING COMPOUNDS AND METHODS -continued RELATED APPLICATIONS - E - --> 0001. This application claims priority under 35 U.S.C. N OPP 2H+2e- OPP " S119(e) to U.S. Provisional Patent Application No. 61/249, OH IPP (3) 929, filed Oct. 8, 2009, which is incorporated herein by ref HMBPP (2) erence in its entirety. GOVERNMENT SUPPORT --. 0002 This invention was made with government support DMAPP (4) under Grant Nos. GM073216, GM65307, and AI074233, awarded by the United States Public Health Service, National 0006. The structure of IspG has not yet been reported, Institutes of Health. The United States Government has cer while two structures have been published for IspH, one from tain rights in the invention. Aquifex aeolicus (Rekittke et al., J. Am. Chem. Soc. 2008, 130, 17206), and the other from E. coli (Grawertet al., Angew: BACKGROUND OF THE INVENTION Chem. Int. Ed. Engl. 2009, 48(31), 5756). According to these 0003 Enzymes that catalyze the formation of isoprenoids reports, both structures contain FeS clusters. However, are of interest as drug targets. The Rohmer pathway, also these observations are in contrast to the conclusions drawn known as the methyl erythritol phosphate or non-mevalonate from both Mössbauer spectroscopy (Xiao et al., J. Am. Chem. pathway, is responsible for isoprenoid biosynthesis in most Soc. 2009, 131 (29), 9931) and EPR spectroscopy (Wolff et pathogenic bacteria and in malaria parasites, such as Plasmo al., FEBS Lett. 2003, 541(1-3), 115). Both spectroscopic dium faciparum (Rohmer et al., Lipids 2008, 43(12), 1095; methods lead to the conclusion that FeS clusters are respon Wiesner and Jomaa, Current Drug Targets 2007, 8(1), 3). sible for catalysis. The same conclusion was arrived at from Enzymes found in the pathway are potentially important as the results of microchemical analyses. It therefore seems anti-infective drug targets because isoprenoids are essential possible that the FeS cluster, while catalytically active, may for Survival of these microorganisms and because the non be relatively labile, as found, for example, inaconitase and in mevalonate pathway is absent in humans (Williams and pyruvate-formation lyase activating factor. To date, there has McCammon, Chem. Biol. Drug Des. 2009, 73(1), 26; de been only one report of an IspH inhibitor (Van Hoof, J. Org. Ruyck and Wouters, Curr. Protein Pept. Sci. 2008, 9(2), 117). Chem. 2008, 73, 1365), which provided an ICso value of -1-2 0004 The structures and mechanisms of action of six of mM. the eight enzymes present in the pathway are now known. 0007 Accordingly, newly identified inhibitors of iso Fosmidomycin, which inhibits the second enzyme in the prenoid biosynthesis enzymes are needed to further study the pathway, has shown promising results for treating malaria Rohmer pathway. New compounds are also needed to (Jomaa et al., Science 1999, 285, (5433), 1573; Borrmannet develop effective therapeutic methods, including methods to al., Antimicrobial Agents and Chemotherapy 2006, 50(8), inhibit the activity of isoprenoid biosynthesis enzymes, and 2713). An inhibitor of one of the six known enzymes, deox methods for treating diseases such as malaria and other infec yxylulose-5-phosphate reductoisomerase, has been used tions, due to increased resistance to currently known antibi clinically to treat both malaria and Pseudomonas aeruginosa Ot1CS. infections (Wiesner et al., Curr: Pharm. Des. 2008, 14, 855: Cheng et al., Biochem. Pharmacol. 1973, 22, 3099). SUMMARY 0005 Less is known, however, about the structures and mechanism of action of the last two enzymes in the pathway: 0008. The invention provides compounds, compositions, IspG and IspH. IspG is E-4-hydroxy-3-methyl-but-2-enyl and methods for treating bacterial infections or parasitic diphosphate (HMBPP) synthase, EC 1.17.1.1, also known as infections. The parasitic infection can be a protozoan infec GcpF. IspH is E-4-hydroxy-3-methyl-but-2-enyl diphos tion, such as malaria. The compounds and compositions can phate (HMBPP) reductase, EC 1.17.1.2, also known as LytB. also be used as antibiotics, for example, to kill bacteria or The penultimate enzyme is IspG, which catalyzes the 2H/ parasites, or to inhibit their growth or proliferation. The 2e reduction of methylerythritol-cyclo-diphosphate invention further provides inhibitors ofisoprenoid biosynthe (MEcPP 1) to HMBPP (2), while the terminal enzyme, IspH, sis enzymes, and methods of inhibiting the activity of iso catalyzes the 2H"/2e reduction of HMBPP (2) to isopentenyl prenoid biosynthesis enzymes. The compounds can be, for diphosphate (IPP 3) and dimethylallyl diphosphate example, alkynyl diphosphate inhibitors of the iron-sulfur (DMAPP 4) in a -5:1 ratio. proteins IspG or IspH (LytB). 0009. Thus, described herein are potent inhibitors of iso prenoid biosynthesis enzymes, such as IspG and IspH. In Some embodiments, the inhibitory compounds include com plexation moieties that include heteroatoms or pie systems that can complex with an FeS cluster of a protein. For example, the inhibitors can contain alkynyl groups that, based on EPR, H, H, C and "Feelectron-nuclear double reso nance (ENDOR) spectroscopy and computational docking, MEcPP (1) form TC/o “metallacycle' complexes with the FeS clusters of IspH. Such clusters have previously been detected by Möss US 2012/0196835 A1 Aug. 2, 2012 bauer and EPR spectroscopy. This complexation and the 0018 each R is independently H, (C-C)alkyl, (C-C) resulting inhibition are of broad general interest because it alkanoyl, or —(C-C)alkyl(aryl); represents the first potent inhibitor of the IspH enzyme, 0019 each R" is independently H, (C-C)alkyl, or (C- together with a novel inhibition mechanism, involving bioor Cs)cycloalkyl: ganometallic complex formation.
Load more

Recommended publications
  • XXXV International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 26–29 May 2015, St Julian's, Malta
    Clinical Toxicology ISSN: 1556-3650 (Print) 1556-9519 (Online) Journal homepage: http://www.tandfonline.com/loi/ictx20 XXXV International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 26–29 May 2015, St Julian's, Malta To cite this article: (2015) XXXV International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 26–29 May 2015, St Julian's, Malta, Clinical Toxicology, 53:4, 233-403, DOI: 10.3109/15563650.2015.1024953 To link to this article: http://dx.doi.org/10.3109/15563650.2015.1024953 Published online: 26 Mar 2015. Submit your article to this journal Article views: 3422 View related articles View Crossmark data Citing articles: 2 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ictx20 Download by: [UPSTATE Medical University Health Sciences Library] Date: 28 December 2016, At: 10:31 Clinical Toxicology (2015), 53, 233–403 Copyright © 2015 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2015.1024953 ABSTRACTS XXXV International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 26–29 May 2015, St Julian ’ s, Malta 1. Modelling dose-concentration-response Introduction: The American Association of Poison Control Cen- ters (AAPCC) published its fi rst annual report in 1983. Call data Ursula Gundert-Remy from sixteen US poison centers was chronicled in that report. Seven submitted data for the entire year. By July 2000, 63 centers Institute for Clinical Pharmacology and Toxicology, Charit é were part of the national poison center system, but only 59 submit- Medical School, Berlin, Germany ted data for the full year.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2011/00284.18 A1 Parker Et Al
    US 2011 002841 8A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/00284.18 A1 Parker et al. (43) Pub. Date: Feb. 3, 2011 (54) USE OF GABBA RECEPTOR ANTAGONISTS Publication Classification FOR THE TREATMENT OF EXCESSIVE SLEEPINESS AND DISORDERS ASSOCATED (51) Int. Cl. WITH EXCESSIVE SLEEPINESS A63L/7028 (2006.01) A 6LX 3/557 (2006.01) (75) Inventors: Kathy P. Parker, Rochester, NY A63L/335 (2006.01) (US); David B. Rye, Dunwoody, A63L/4355 (2006.01) GA (US); Andrew Jenkins, A63L/047 (2006.01) Decatur, GA (US) A6IP 25/00 (2006.01) Correspondence Address: (52) U.S. Cl. ........... 514/29: 514/220; 514/450, 514/291; FISH & RICHARDSON P.C. (AT) 5147738 P.O BOX 1022 Minneapolis, MN 55440-1022 (US) (57) ABSTRACT (73) Assignee: Emory University, Atlanta, GA GABA receptor mediated hypersomnia can be treated by (US) administering a GABA receptor antagonist (e.g., flumazenil; clarithromycin; picrotoxin; bicuculline; cicutoxin; and (21) Appl. No.: 12/922,044 oenanthotoxin). In some embodiments, the GABA receptor antagonist is flumazenil or clarithromycin. The GABA (22) PCT Filed: Mar. 12, 2009 receptor mediated hypersomnia includes shift work sleep disorder, obstructive sleep apnea/hypopnea syndrome, narco (86). PCT No.: PCT/USO9/37034 lepsy, excessive sleepiness, hypersomnia (e.g., idiopathic hypersomnia; recurrent hyperSonmia; endozepine related S371 (c)(1), recurrent stupor; and amphetamine resistant hyperSonmia), (2), (4) Date: Sep. 10, 2010 and excessive sleepiness associated with shift work sleep disorder, obstructive sleep apnea/hypopnea syndrome, and Related U.S. Application Data hypersomnia (e.g., idiopathic hypersomnia; recurrent hyper (60) Provisional application No.
    [Show full text]
  • 1-Iodo-1-Pentyne
    MIAMI UNIVERSITY-THE GRADUATE SCHOOL CERTIFICATE FOR APPROVING THE DISSERTATION We hereby approve the Dissertation of Lizhi Zhu Candidate for the Degree: Doctor of Philosophy ________________________________ Robert E. Minto, Director ________________________________ John R. Grunwell, Reader ________________________________ John F. Sebastian, Reader ________________________________ Ann E. Hagerman, Reader ________________________________ Richard E. Lee, Graduate School Representative ABSTRACT INVESTIGATING THE BIOSYNTHESIS OF POLYACETYLENES: SYNTHESIS OF DEUTERATED LINOLEIC ACIDS & MECHANISM STUDIES OF DMDS ADDITION TO 1,4-ENYNES By Lizhi Zhu A wide range of polyacetylenic natural products possess antimicrobial, antitumor, and insecticidal properties. The biosyntheses of these natural products are widely distributed among fungi, algae, marine sponges, and higher plants. As details of the biosyntheses of these intriguing compounds remains scarce, it remains important to develop molecular probes and analytical methods to study polyacetylene secondary metabolism. An effective pathway to prepare selectively deuterium-labeled linoleic acids was developed. By this Pd-catalyzed method, deuterium can be easily introduced into the vinyl position providing deuterolinoleates with very high isotopic purity. This method also provides a general route for the construction of 1,4-diene derivatives with different chain lengths and 1,4-diene locations. Linoleic acid derivatives (12-d, 13-d and 16,16,17,17,18,18,18-d7) were synthesized according to this method. A stereoselective synthesis of methyl (14Z)- and (14E)-dehydrocrepenynate was achieved in five to six steps that employed Pd-catalyzed cross-coupling reactions to construct the double bonds between C14 and C15. Compared with earlier methods, the improved syntheses are more convenient (no spinning band distillations or GLC separation of diastereomers were necessary) and higher Z/E ratios were obtained.
    [Show full text]
  • Fall TNP Herbals.Pptx
    8/18/14 Introduc?on to Objecves Herbal Medicine ● Discuss history and role of psychedelic herbs Part II: Psychedelics, in medicine and illness. Legal Highs, and ● List herbs used as emerging legal and illicit Herbal Poisons drugs of abuse. ● Associate main plant and fungal families with Jason Schoneman RN, MS, AGCNS-BC representave poisonous compounds. The University of Texas at Aus?n ● Discuss clinical management of main toxic Schultes et al., 1992 compounds. Psychedelics Sacraments: spiritual tools or sacred medicine by non-Western cultures vs. Dangerous drugs of abuse vs. Research and clinical tools for mental and physical http://waynesword.palomar.edu/ww0703.htm disorders History History ● Shamanic divinaon ○ S;mulus for spirituality/religion http://orderofthesacredspiral.blogspot.com/2012/06/t- mckenna-on-psilocybin.html http://www.cosmicelk.net/Chukchidirections.htm 1 8/18/14 History History http://www.10zenmonkeys.com/2007/01/10/hallucinogenic- weapons-the-other-chemical-warfare/ http://rebloggy.com/post/love-music-hippie-psychedelic- woodstock http://fineartamerica.com/featured/misterio-profundo-pablo- amaringo.html History ● Psychotherapy ○ 20th century: un;l 1971 ● Recreaonal ○ S;mulus of U.S. cultural revolu;on http://qsciences.digi-info-broker.com http://www.uspharmacist.com/content/d/feature/c/38031/ http://en.wikipedia.org/nervous_system 2 8/18/14 Main Groups Main Groups Tryptamines LSD, Psilocybin, DMT, Ibogaine Other Ayahuasca, Fly agaric Phenethylamines MDMA, Mescaline, Myristicin Pseudo-hallucinogen Cannabis Dissociative
    [Show full text]
  • Is Palatability of a Root-Hemiparasitic Plant Influenced by Its Host Species?
    Oecologia (2005) 146: 227–233 DOI 10.1007/s00442-005-0192-3 PLANTANIMALINTERACTIONS Martin Scha¨dler Æ Mareike Roeder Æ Roland Brandl Diethart Matthies Is palatability of a root-hemiparasitic plant influenced by its host species? Received: 16 November 2004 / Accepted: 21 June 2005 / Published online: 19 July 2005 Ó Springer-Verlag 2005 Abstract Palatability of parasitic plants may be influ- Introduction enced by their host species, because the parasites take up nutrients and secondary compounds from the hosts. If Parasitic plants attack shoots or roots of other plants and parasitic plants acquired the full spectrum of secondary take up water, nutrients and solutes from the hosts by compounds from their host, one would expect a corre- means of specialized contact organs (haustoria, Kuijt lation between host and parasite palatability. We 1969). About 1% of all plants are parasitic and parasitic examined the palatability of leaves of the root-hemi- plants are common components of many plant commu- parasite Melampyrum arvense grown with different host nities (Molau 1995). The majority of parasitic plants are plants and the palatability of these host plants for two actually hemiparasites that have green leaves and are generalist herbivores, the caterpillar of Spodoptera lit- able to photosynthesize (Kuijt 1969). Parasitic plants can toralis and the slug Arion lusitanicus. We used 19 species drastically reduce the growth of their host plants and of host plants from 11 families that are known to con- some are important agricultural pests (Parker and Riches tain a wide spectrum of anti-herbivore compounds. 1993; Pennings and Callaway 2002). Because parasitic Growth of M.
    [Show full text]
  • Cicuta Douglasii) Tubers
    Toxicon 108 (2015) 11e14 Contents lists available at ScienceDirect Toxicon journal homepage: www.elsevier.com/locate/toxicon Short communication The non-competitive blockade of GABAA receptors by an aqueous extract of water hemlock (Cicuta douglasii) tubers * Benedict T. Green a, , Camila Goulart b, 1, Kevin D. Welch a, James A. Pfister a, Isabelle McCollum a, Dale R. Gardner a a Poisonous Plant Research Laboratory, Agricultural Research Service, United States Department of Agriculture, Logan, UT, USA b Graduate Program in Animal Science, Universidade Federal de Goias, Goiania,^ Goias, Brazil article info abstract Article history: Water hemlocks (Cicuta spp.) are acutely toxic members of the Umbellierae family; the toxicity is due to Received 22 July 2015 the presence of C17-polyacetylenes such as cicutoxin. There is only limited evidence of noncompetitive Received in revised form antagonism by C17-polyacetylenes at GABAA receptors. In this work with WSS-1 cells, we documented 9 September 2015 the noncompetitive blockade of GABA receptors by an aqueous extract of water hemlock (Cicuta dou- Accepted 14 September 2015 A glasii) and modulated the actions of the extract with a pretreatment of 10 mM midazolam. Available online 28 September 2015 Published by Elsevier Ltd. Keywords: Water hemlock Cicutoxin C17-polyacetylenes Benzodiazepines Barbiturates Midazolam Water hemlocks (Cicuta spp.) are acutely toxic members of the antagonists of the GABAA receptor by binding to the picrotoxin Umbellierae, or carrot family, that grow in wet habitats such as binding site within the chloride channel to block ion flow through streambeds or marshlands, and have been considered one of the the channel (Ratra et al., 2001; Chen et al., 2006; 2011; Olsen, most toxic plants of North America for many years (Kingsbury, 2006).
    [Show full text]
  • Neurochemical and Behavioral Features in Genetic Absence Epilepsy and in Acutely Induced Absence Seizures
    Hindawi Publishing Corporation ISRN Neurology Volume 2013, Article ID 875834, 48 pages http://dx.doi.org/10.1155/2013/875834 Review Article Neurochemical and Behavioral Features in Genetic Absence Epilepsy and in Acutely Induced Absence Seizures A. S. Bazyan1 and G. van Luijtelaar2 1 Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Science, Russian Federation, 5A Butlerov Street, Moscow 117485, Russia 2 Biological Psychology, Donders Centre for Cognition, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, P.O. Box 9104, 6500 HE Nijmegen, The Netherlands Correspondence should be addressed to G. van Luijtelaar; [email protected] Received 21 January 2013; Accepted 6 February 2013 Academic Editors: R. L. Macdonald, Y. Wang, and E. M. Wassermann Copyright © 2013 A. S. Bazyan and G. van Luijtelaar. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The absence epilepsy typical electroencephalographic pattern of sharp spikes and slow waves (SWDs) is considered to be dueto an interaction of an initiation site in the cortex and a resonant circuit in the thalamus. The hyperpolarization-activated cyclic nucleotide-gated cationic Ih pacemaker channels (HCN) play an important role in the enhanced cortical excitability. The role of thalamic HCN in SWD occurrence is less clear. Absence epilepsy in the WAG/Rij strain is accompanied by deficiency of the activity of dopaminergic system, which weakens the formation of an emotional positive state, causes depression-like symptoms, and counteracts learning and memory processes.
    [Show full text]
  • Studying GABAA Receptors Using AII Amacrine Cells in the Rat Retina by Tuan Van Trinh
    Studying GABAA Receptors using AII Amacrine Cells in the Rat Retina By Tuan Van Trinh MASTER THESIS IN PHARMACY Department of Biomedicine/ Centre for Pharmacy University of Bergen May 2018 The picture of AII amacrine cells in front page is adapted from Zhou et al., 2016. 2 ACKNOWLEDGEMENTS This study was carried out at the department of Biomedicine, University of Bergen, during the period August 2012 to April 2013. Due to a serious illness, the project was interrupted, and continued again in April 2018 to May 2018. I would like to thank several people for their support during this project. First I would like to express my sincere gratitude to my supervisor prof. Ph.d Margaret Lin Veruki and co-supervisor prof. dr. med. Espen Hartveit for valuable advice and much appreciated guidance during the period. Ph.d. Yifan Zhou is thanked for helping me with collecting the data, and of course thanks to Marte Nørve Årvik, Lise Skålvik Amble and all my co-workers and lab personnel that have helped me during this period. To my family and my friends thank you for supporting me during this hard period of life. Bergen, May 2018 3 TABLE OF CONTENTS ACKNOWLEDGEMENTS……………………………………………………..3 TABLE OF CONTENTS………………………………………………………..4 ABBREVIATIONS……...………………………………………………………8 AIMS……………………...…………………………………………………....11 SUMMARY……………………...…………………………………………….13 1.0 INTRODUCTION AND THEORY……………………………………………16 1.1 Nerve cell and signal communication ………………………………16 1.1.1 Cell membrane……………………………..……………………...17 1.1.2 The membrane potential………….…………………….……….……..18 1.1.3 The
    [Show full text]
  • Natural Agents Affecting Excitatory and Inhibitory Neurotransmission
    Natural Agents Affecting Excitatory and Inhibitory Neurotransmission Adenosine Receptor Glycine Receptor Antagonists: K Channel Antagonists: Na Channel Agents: Antagonists: • Oenanthe fistulosa (Water Dropwort) [Toxin] • Cicutoxin/Cicuta maculata (Water • Aconitine/Aconitum spp • Caffeine • Strychnine/Strychnos Nux Vomica Hemlock) AND Cicuta Virosa (Monkshood/Wolfsbane) (Cowbane or Northern Water Hemlock) • Taxine/Taxus (Yew) Ca Cl Cl Na Adenosine Adenosine Glycine DA/NE/E/S PRE-SYNAPTIC POST-SYNAPTIC K + Glutamate Other Glutamate GABA (NMDA, KA) O PLP CO O Sympathomimetics: Na +/- Ca 2 Cl + + INHIBITORY NEURON • Cathinones (Khat/Qat) H3N H3N O- O- • Cocaine/Coca Glutamic acid • Ephedra/Ephedra spp. (Ma Huang) EXCITATORY NEURON-O O decarboxylase Competitive Non-competitive • Synanceia (Stonefish) [Toxin] Glutamate Agonists: Glutamate GABA Antagonists: Antagonists: • β-N-oxalylamino-L-alanine • Bicuculline/Dicentra • Anisatin/Illicium anisatum Serotonergics: (BOAA)/Lathyrus Sativa cucullaria (Dutchman's (Japanese star anise) GAD Inhibitors: breeches) • Cicutoxin & Virol A/ Cicuta • Hypericum perforatum/ St. (Chickling Pea) • Cyanide/cyanogenic glycosides • Colchicine/Colchicum maculata (Water Hemlock) AND John's Wort • Domoic Acid/Pseudo-nitzschia australis [Amnestic Shellfish [Stonefruit] autumnale (Autumn crocus) Cicuta Virosa (Cowbane or Poisoning] • Domoic Acid/Pseudo-nitzschia • Oenanthe fistulosa (Water Northern Water Hemlock) • Ibotenic Acid/Amanita Muscaria australis [Amnestic Shellfish Dropwort) [Toxin] *Probably • Picrotoxin/Anamirta
    [Show full text]
  • Federal Register/Vol. 66, No. 139/Thursday, July 19, 2001/Rules
    37830 Federal Register / Vol. 66, No. 139 / Thursday, July 19, 2001 / Rules and Regulations Indian Tribal Governments (63 FR expected to affect energy supply, ENVIRONMENTAL PROTECTION 27655, May 19, 1998), do not apply to distribution, or use. AGENCY this rule. Executive Order 13175, entitled Consultation and Coordination XII. Submission to Congress and the 40 CFR Part 174 with Indian Tribal Governments (65 FR Comptroller General [OPP–300368B; FRL–6057–6] 67249, November 6, 2000), which took The Congressional Review Act, 5 effect on January 6, 2001, revokes U.S.C. 801 et seq., as added by the Small RIN 2070–AC02 Executive Order 13084 as of that date. Business Regulatory Enforcement EPA developed this rulemaking, Exemption From the Requirement of a Fairness Act of 1996, generally provides however, during the period when Tolerance Under the Federal Food, that before a rule may take effect, the Executive Order 13084 was in effect; Drug, and Cosmetic Act for Residues thus, EPA addressed tribal agency promulgating the rule must Derived Through Conventional considerations under Executive Order submit a rule report, which includes a Breeding From Sexually Compatible 13084. For the same reasons stated for copy of the rule, to each House of the Plants of Plant-Incorporated Executive Order 13084, the Congress and to the Comptroller General Protectants (Formerly Plant- requirements of Executive Order 13175 of the United States. EPA will submit a Pesticides) do not apply to this rule either. For the report containing this rule and other same reasons, this rule does not have required information to the U.S. Senate, AGENCY: Environmental Protection any substantial direct effect on States, the U.S.
    [Show full text]
  • Dissertation
    DISSERTATION Titel der Dissertation „Isolation of positive, allosteric GABAA receptor modulators from Chinese herbal drugs traditionally used in the treatment of anxiety and insomnia“ Verfasserin Mag. pharm. Judith Singhuber angestrebter akademischer Grad Doktorin der Naturwissenschaften (Dr.rer.nat.) Wien, 2011 Studienkennzahl lt. A 091 449 Studienblatt: Dissertationsgebiet lt. Dr.-Studium der Naturwissenschaften Pharmazie Studienblatt: Betreuerin / Betreuer: Univ. Prof. Mag. Dr. Brigitte Kopp For Maximillian & Lennox ACKNOWLEDGMENTS In this place I would like to thank the people which contributed to the success of my thesis: Prof. Brigitte Kopp, my supervisor, for providing an interesting topic and for her guidance. Prof. Steffen Hering (Department of Pharmacology and Toxicology, University of Vienna) for the possibility to work in his Department. Dr. Igor Baburin (Department of Pharmacology and Toxicology, University of Vienna) for the pharmacological investigations on the 56 extracts and the HPLC fractions of A. macrocephala and C. monnieri. Dr. Sophia Khom (former Department of Pharmacology and Toxicology, University of Vienna) for her assistance as well as interesting discussions on GABAergic neurotransmission and other topics. Prof. Gerhard F. Ecker (Department of Medicinal Chemistry) for the binary QSAR and help with the pharmacophore model. Prof. Ernst Urban (Department of Medicinal Chemistry, University of Vienna) und Prof. Hanspeter Kählig (Institute of Organic Chemistry, University of Vienna) for the NMR- measurements. Dr.
    [Show full text]
  • Natural Agents Affecting Excitatory and Inhibitory Neurotransmission: Adenosine Receptor Antagonism: Caffeine (Coffea Spp/C
    Natural Agents Affecting Excitatory and Inhibitory Neurotransmission: Adenosine receptor antagonism: ● Caffeine (Coffea spp/Coffee) Primary GABA inhibition: ● Anisatin (Japanese star anise/Illicium anisatum) ○ non-competitive GABA (channel) inhibition 1’2 ● Bicuculline (Dicentra cucullaria/Dutchman's breeches) ○ competitive inhibition GABA site ○ (and probably non-competitive via allosteric change) 3 ● Cicuta maculata (Water Hemlock) & Cicuta Virosa (Cowbane or Northern Water Hemlock) ○ Cicutoxin- GABA +/- inhibition potassium channels 4’5 ○ Virol A: non-competitive with GABA binding site, but does produce competitive GABA channel (chloride) inhibition ■ structurally similar to cicutoxin 6 ● Colchicine (Colchicum autumnale/autumn crocus) ○ competitive antagonist 7 ● Oenanthe fistulosa (Water Dropwort) [Toxin] ○ probably competitive inhibition of GABA Chloride channel (dose dependent blockade) ○ structure similar to cicutoxin ○ from island of Sardinia; ? glycine antagonism- risus sardonicus 8 ● Picrotoxin (Anamirta cocculus/Fishberries) ○ non-competitive inhibition 9 1 Rietjens IM, Martena MJ, Boersma MG, et al. Molecular mechanisms of toxicity of important food-borne phytotoxins. Molecular mechanisms of toxicity of important food-borne phytotoxins. Mol Nutr Food Res. 2005 Feb;49(2):131-58. PMID: 15635687 2 Perret C, Tabin R, Marcoz JP et al. [Apparent life-threatening event in infants: think about star anise intoxication!]. [Article in French] Arch Pediatr. 2011 Jul;18(7):750-3. doi: 10.1016/j.arcped.2011.03.024. 3 Ueno S, Bracamontes J, Zorumski C, et al. Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor. J Neurosci. 1997 Jan 15;17(2):625-34.PMID: 8987785 4 Schep LJ, Slaughter RJ, Becket G, Beasley DM. Poisoning due to water hemlock. Clin Toxicol (Phila). 2009 Apr;47(4):270-8.
    [Show full text]