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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. Martin Zehl (Department of Pharmacognosy, University of Vienna) for the MS- measurements. All my colleagues and friends, especially Maga Sylvia Vogl und Maga Kerstin Kainz as well as my family for providing help and encouragement throughout this time. ABBREVIATIONS 5-HT3 receptor 5-hydroxytryptamine type 3 receptor ACh acetyl choline ASR anisaldehyde sulphuric acid reagent ATF4/CREB activating transcription factor 4/cAMP-response element binding protein 2 BIG2 brefeldin A-inhibited GDP/GTP exchange factor 2 BZ benzodiazepine CAM complementary and alternative medicine CC column chromatography cF cumulative fraction CHM Chinese Herbal Medicine CHOP CCAAT/enhancer binding protein (C/EBP), epsilon homologous protein CM Chinese Medicine CNS central nervous system DAD diode array detector DEPC diethylpyrocarbonate DZP diazepam EBOB ethynylbicycloorthobenzoate ELSD evaporative light scattering detector EPM elevated plus maze ESI electro spray ionization EtOAc ethyl acetate FLZ flumazenil GABA γ-aminobutyric acid GABAA receptor GABA type A receptor GABAB receptor GABA type B receptor GABARAP GABAA receptor adaptor protein GABA-T GABA transaminase GAD glutamate dehydrogenase GAT GABA transporter GODZ Golgi specific DHHC zinc finger GPCR G protein coupled receptor GRIF 1 GABAA receptor interacting factor-1 GRIP glutamate receptor interacting protein HAc acetic acid HAP huntingtin associated protein HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC high performance liquid chromatography IGABA GABA-induced chloride current LGIC ligand gated ion channel MeCN acetonitrilee MeOH methanol MS mass spectrometer/mass spectrometry msec7-1 mammalian homologue of yeast sec7p-1 n ACh receptor nicotinic acetyl choline receptor NMR nuclear magnet resonance NSF n-ethylmaleimide sensitive fusion protein (or receptor) pA pro Analysis PE petroleum ether Plic-1 protein linking IAP (CD74) to cytoskeleton-1 PRIP PLC-related catalytically inactive protein PTX picrotoxin(in) PTZ pentylenetetrazol Rf retention factor S.E.M standard error of the mean SSADH succinic semialdehyde dehydrogenase TBPS t-butylbicyclophosphorothionate THPROG tetrahydroprogesterone TLC thin layer chromatography TM transmembrane domain VGAT vesicular GABA transporter VLC vacuum liquid chromatography 1 INTRODUCTION .................................................................................................................1 1.1 Natural products in drug discovery..................................................................................1 1.2 γ-Aminobutyric acid (GABA)............................................................................................2 1.2.1 The GABAA receptor...................................................................................................4 1.2.2 The GABAB receptor.................................................................................................13 1.3 Natural compounds as GABAA receptor ligands...........................................................14 1.4 Aim of the study................................................................................................................22 2 MATERIAL AND METHODS ..........................................................................................23 2.1 Plant material....................................................................................................................23 2.3 Extraction..........................................................................................................................24 2.3.1 Extracts for initial screening ....................................................................................24 2.3.2 n-Hexane extract from Atractylodes macrocephala.................................................24 2.3.3 Ethyl acetate (EtOAc) extract from Juncus effusus...............................................24 2.4 Chromatography 2.4.1 Thin Layer Chromatography (TLC) .....................................24 2.4.2 Column Chromatography (CC) ...............................................................................25 2.4.3 Vacuum Liquid Chromatography (VLC) ...............................................................26 2.4.5 High Performance Liquid Chromatography (HPLC) ...........................................27 2.5 Mass Spectrometry (MS) .................................................................................................28 2.6 Nuclear Magnetic Resonance Spectroscopy (NMR) .....................................................28 2.6.1 NMR of atractylenolide II and III ...........................................................................28 2.6.1 NMR of atractylenolide I, osthole, imperatorin, effusol and dehydroeffusol ......28 2.7 Expression of GABAA Receptors in Xenopus laevis oocytes .........................................28 2.8 Two-microelectrode voltage clamp technique and automated fast perfusion system 29 2.9 Data Analysis and statistics .............................................................................................29 2.10. Molecular modeling.......................................................................................................29 3 RESULTS.............................................................................................................................30 3.1 Isolation of the active principles from Atractylodes macrocephala Koidz. ..................30 3.2 GABAA receptor modulators from Chinese Herbal Medicines traditionally applied against insomnia and anxiety (manuscript) .........................................................................39 3.3 Isolation of the active principles of Cnidium monnieri (L.) Cuss. ex Juss. ..................56 3.4 Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins (manuscript)...................................................................63 3.5 Isolation of the active principles from Juncus effusus L. ............................................. 84 3.6 GABAA receptor modulators from the Chinese herbal drug Junci Medulla, the pith of Juncus effusus L. (manuscript) ........................................................................................ 93 4 DISCUSSION .................................................................................................................... 107 5 SUMMARY ....................................................................................................................... 116 6 ZUSAMMENFASSUNG .................................................................................................. 117 7 REFERENCES ANNEX I: NMR DATA FOR ATRACTYLENOLIDE III ANNEX II: NMR DATA FOR ATRACTYLENOLIDE II ANNEX III: NMR DATA FOR ATRACTYLENOLIDE I ANNEX IV: NMR DATA FOR OSTHOLE ANNEX V: NMR DATA FOR IMPERATORIN ANNEX VI: NMR DATA FOR EFFUSOL ANNEX VII: NMR DATA FOR DEHYDROEFFUSOL CURRICULUM VITAE 1 INTRODUCTION 1 Introduction 1.1 Natural products in drug discovery Plants have always been a good source for (small molecule) drugs, since they produce a wide range of bioactive primary and secondary metabolites. Conservatively estimated, natural products (NPs) and products derived thereof including semi-synthetic drugs and natural product-mimetics, still account for approximately 30 % of all newly approved drugs between 1981 and 2006 (Fig. 1; Harvey et al., 2010; Newman, 2008; Potterat et al., 2008). Furthermore, the impact of natural products on our knowledge about basic biological processes can be recognized in the great variety of drug targets that are named after compounds from natural origin like µ-(morphine)-opioid, nicotinic and muscarinic acetyl choline-, cannabinoid-, or kainate receptor. Figure 1. Natural products in drug discovery. The pie chart displays all new chemical entities approved as drugs between 1981 and 2006. “B” Biological; usually a large (>45 residues) peptide or protein either isolated from an organism/cell line or produced by biotechnological means in a surrogate host. “N”
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