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Discovery of New Scaffolds for GABAA Receptor Modulators from Natural Origin

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Discovery of New Scaffolds for GABAA Receptor Modulators from Natural Origin Discovery of New Scaffolds for GABAA Receptor Modulators from Natural Origin Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Janine Michèle Zaugg aus Trub, Bern Basel, 2011 Original document stored on the publication server of the University of Basel edoc.unibas.ch This work is licenced under the agreement „Attribution Non-Commercial No Derivatives – 2.5 Switzerland“. The complete text may be viewed here: creativecommons.org/licenses/by-nc-nd/2.5/ch/deed.en Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Matthias Hamburger Prof. Dr. Veronika Butterweck Basel, den 21.06.2011 Prof. Dr. Martin Spiess Dekan Attribution-Noncommercial-No Derivative Works 2.5 Switzerland You are free: to Share — to copy, distribute and transmit the work Under the following conditions: Attribution. You must attribute the work in the manner specified by the author or licensor (but not in any way that suggests that they endorse you or your use of the work). Noncommercial. You may not use this work for commercial purposes. No Derivative Works. You may not alter, transform, or build upon this work. • For any reuse or distribution, you must make clear to others the license terms of this work. The best way to do this is with a link to this web page. • Any of the above conditions can be waived if you get permission from the copyright holder. • Nothing in this license impairs or restricts the author's moral rights. Your fair dealing and other rights are in no way affected by the above. This is a human-readable summary of the Legal Code (the full license) available in German: http://creativecommons.org/licenses/by-nc-nd/2.5/ch/legalcode.de Disclaimer: The Commons Deed is not a license. It is simply a handy reference for understanding the Legal Code (the full license) — it is a human-readable expression of some of its key terms. Think of it as the user-friendly interface to the Legal Code beneath. This Deed itself has no legal value, and its contents do not appear in the actual license. Creative Commons is not a law firm and does not provide legal services. Distributing of, displaying of, or linking to this Commons Deed does not create an attorney-client relationship. Quelle: http://creativecommons.org/licenses/by-nc-nd/2.5/ch/deed.en Datum: 3.4.2009 Table of Contents LIST OF ABBREVIATIONS 7 SUMMARY 9 ZUSAMMENFASSUNG 11 1. AIM OF THE WORK 13 2. INTRODUCTION 17 2.1. Lead Finding from Nature 18 2.2. Identification and Structural Characterization of Bioactive Plant-derived Natural Products 21 Screening of Plant Extracts for Bioactivity 21 Isolation of Bioactive Natural Products 21 Structure Elucidation of Natural Products 24 The Challenge of the Absolute Configuration 25 2.3. The GABAA Receptor 29 In vitro Bioassays to Assess GABAA Receptor Activity 32 Behavioral Models for GABAA Receptor Related Pharmacological Effects 35 2.4. Natural Products as GABAA Receptor Modulators 39 Flavonoids with GABAA Receptor Activity 39 Terpenoids with GABAA Receptor Activity 40 Alkaloids with GABAA Receptor Activity 41 Miscellanous Structural Classes with GABAA Receptor Activity 42 3. RESULTS AND DISCUSSION 45 3.1. HPLC-based Activity Profiling: Discovery of Piperine as a Positive GABAA Receptor Modulator Targeting a Benzodiazepine-Independent Binding Site 47 3.2. HPLC-based Activity Profiling of Angelica pubescens Roots for New Positive GABAA Receptor Modulators in Xenopus Oocytes 71 3.3. Positive GABAA Receptor Modulators from Acorus calamus and Structural Analysis of (+)- Dioxosarcoguaiacol by 1D and 2D NMR and Molecular Modeling 87 3.4. Identification and Characterization of GABAA Receptor Modulatory Diterpenes from Biota orientalis That Decrease Locomotor Activity in Mice 109 3.5. Identification of GABAA Receptor Modulators in Kadsura longipedunculata and Assignment of Absolute Configurations by Quantum-chemical ECD Calculations 155 4. CONCLUSIONS AND OUTLOOK 189 ACKNOWLEDGMENTS / DANKSAGUNGEN 196 LIST OF ABBREVIATIONS BBB Blood-brain barrier BW Bodyweight BZD Benzodiazepine CD Circular dichroism CD50 Half maximal convulsant concentration CHO cells Chinese Hamster Ovary cells CNS Central nervous system DMSO Dimethyl sulfoxide EC50 Half maximal effective concentration ECD Electronic circular dichroism ELSD Evaporative light scattering detection FDA Food and Drug Administration GABA Gammaaminobutyric acid GABAA receptor Gammamaniobutyric acid type A receptor HEK cells Human endothelial kidney cells hERG Human ether-a-go-go related gene HPLC High performance liquid chromatography HTS High-througput screening IR spectroscopy Infrared spectroscopy LGIC Ligand gated ion channels LTK- cells Leukocyte tyrosine kinase cells MS Mass spectrometry NDA New drug approval NMR spectroscopy Nuclear magnetic resonance spectroscopy NP Natural product PDA detector Photo-diode array detector TCM Traditional Chinese medicine TEVC Two-microelectrode voltage clamp TOF Time-of-flight UV spectrum Ultraviolet light spectrum VIS spectrum Visible light spectrum 7 8 SUMMARY Gamma-aminobutyric acid type A (GABAA) receptors are the major inhibitory neurotransmitter receptors in the central nervous system (CNS). These heteropentameric transmembrane proteins act as chloride ion channel upon activation by the endogenous ligand γ- amino butyric acid (GABA). Until now, 11 distinct GABAA receptor subtypes have been identified in the human brain. They differ in their subunit stoichiometry, tissue localization, functional characteristics, and pharmacological properties. Many CNS depressant drugs, such as the benzodiazepines exert their action via enhancement of the GABAergic neuronal inhibition. However, therapy may be accompanied by unwanted side-effects and specific clinical action is precluded due to the lack of GABAA receptor subtype selectivity. In a preliminary screen the lipophilic extracts of Piper nigrum fruits, Angelica pubescens roots, Acorus calamus roots, Biota orientalis leaves and twigs, and Kadsura longipedunculata fruits had shown positive GABAA receptor modulating activity in an in vitro functional, automated two-microelectrode voltage clamp assay with Xenopus laevis oocytes, which transiently expressed α1β2γ2S GABAA receptors. Aiming at the discovery of new scaffolds which act at the GABAA receptor, the active constituents of these five plant extracts were identified by means of an HPLC-based activity profiling approach. In total, we discovered 28 secondary metabolites with positive GABAA receptor modulating properties belonging to the structural classes of coumarins, monoterpenes, sesquiterpenes, diterpenes, phenylpropanes, piperamides, and lignans. Their structures were elucidated by a combination of powerful analytical methods such as HPLC-PDA-TOF-MS, highly sensitive microprobe NMR, and for chiral compounds, polarimetry and ECD. Determination of relative and absolute configuration was supported by conformational analysis and quantum chemical calculations. Furthermore, three yet unknown natural products could be identified. HPLC-based activity profiling with P. nigrum enabled the identification of 13 structurally related piperamides with minimum amount of extract. This allowed us to draw preliminary structure activity considerations for the scaffold of piperine, which was the main α1β2γ2S GABAA receptor modulator in this plant (EC50: 52.4 ± 9.4 μM, maximal stimulation of GABA induced chloride currents (IGABA) by 302% ± 27%). 9 Sandaracopimaric acid and isopimaric acid from B. orientalis were tested for subtype selectivity at α1-3,5β1-3γ2S subtypes which revealed a comparatively high efficiency of both compounds at α2/3-subunit containing receptors. Additionally, sandaracopimaric acid exerted superior efficiency at receptors comprising β2-subunits. It showed EC50 values from 24.9 ± 6.3 μM to 82.2 ± 46.6 μM, and efficiencies ranging between 502% ± 56% to 1101% ± 98% potentiation of IGABA at the subtypes of investigation. A decrease of locomotor activity in the Open Field behavioral model was observed after intraperitoneal injection of 3 to 30 mg sandaracopimaric acid per kg bodyweight in mice. A trend towards anxiolytic-like activity could be observed with 1 and 3 mg/kg. Further “drug-like” GABAA receptor modulating scaffolds were discovered among the lignans from K. longipedunculata (potencies down to 12.8 ± 3.1 μM and efficiencies up to 886 ± 291% stimulation of IGABA) and among the sesquiterpenes from A. calamus (potencies down to 34.0 ± 6.7 μM and efficiencies up to 886 ± 105% stimulation of IGABA). These substances have potential for the further development as therapeutics acting at the GABAA receptor. 10 ZUSAMMENFASSUNG Gamma-Aminobuttersäure Typ A (GABAA) Rezeptoren sind die wichtigsten inhhibitorischen Rezeptoren im zentralen Nervensystem. Neunzehn verschiedene GABAA Rezeptor Untereinheiten können in unterschiedlicher Stöchiometrie zu Heteropentameren (GABAA Rezeptor Subtypen) konglomerieren und so transmembranäre Chloridionenkanäle bilden, die durch den endogenen Liganden γ-Aminobuttersäure (GABA) aktiviert und dadurch geöffnet werden. Bisher konnten 11 verschiedene GABAA-Rezeptor-Subtypen im menschlichen Gehirn identifiziert werden. Diese unterscheiden sich in ihrer Gewebe-Lokalisierung und ihren funktionellen und pharmakologischen Eigenschaften. Viele zentraldämpfende Medikamente, wie z.B. die Benzodiazepine üben ihre Wirkung über die Verstärkung der GABAergen Hemmung neuronaler Schaltkreise aus. Die Therapie mit diesen Wirkstoffen
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