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Molecular Analysis of the Interaction of the Four Histamine Receptor Subtypes with Antidepressant and Antipsychotic Drugs

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Molecular Analysis of the Interaction of the Four Histamine Receptor Subtypes with Antidepressant and Antipsychotic Drugs Molecular analysis of the interaction of the four histamine receptor subtypes with antidepressant and antipsychotic drugs Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) der Fakultät für Chemie und Pharmazie der Universität Regensburg vorgelegt von Heidrun Appl aus Regensburg 2010 Der experimentelle Teil dieser Arbeit entstand in der Zeit von Januar 2007 bis April 2010 unter Leitung von Herrn Prof. Dr. R. Seifert am Institut für Pharmakologie und Toxikologie der Naturwissenschaftlichen Fakultät IV – Chemie und Pharmazie – der Universität Regensburg. Das Promotionsgesuch wurde eingereicht im September 2010. Tag der mündlichen Prüfung: 29. Oktober 2010 Prüfungsausschuss: Prof. Dr. Dr. W. Wiegrebe (Vorsitzender) Prof. Dr. R. Seifert (Erstgutachter) Prof. Dr. Dr. E. Haen (Zweitgutachter) Prof. Dr. J. Heilmann (Drittprüfer) für Tobias Danksagungen An dieser Stelle möchte ich ganz herzlich all den Menschen danken, die zum Gelingen dieser Arbeit beigetragen haben: Herrn Prof. Dr. Roland Seifert für die Gelegenheit, an einem so interessanten und vielseitigen Projekt arbeiten zu dürfen, für seine kompetente fachliche Anleitung, die hilfreichen Ratschläge und Ideen, für seine ehrliche und freundliche Art und seine konstruktive Kritik beim Verfassen dieser Arbeit. Vielen Dank für die entgegengebrachte Geduld und das Vertrauen! Herrn Prof. Dr. Dr. Ekkehard Haen für seine wissenschaftlichen Anregungen im Bereich des Therapeutischen Drug Monitorings und die Erstellung des Zweitgutachtens, Herrn Prof. Dr. Jörg Heilmann für die Übernahme des Amtes des Drittprüfers und Herrn Prof. Dr. Dr. Wolfgang Wiegrebe für den Vorsitz in der Prüfungskommission, Frau Dr. Andrea Straßer für die Bereitstellung ihrer Expertise und das Molecular Modelling zum H1 und H4 Rezeptor sowie für die wissenschaftlichen Ratschläge, Herrn Tobias Holzammer für die Durchführung des Molecular Modellings der H2 Rezeptor‐ modelle und für die Hilfestellung bei der Interpretation der Aufnahmen sowie Herrn Prof. Dr. Stefan Dove für seine fachliche Unterstützung, Herrn Michael J. Keiser von der University of California, San Francisco, USA für die Durchführung des Similarity Ensemble Approach und für die Hilfestellung bei der Interpretation der Aufnahmen, Herrn Dr. Erich Schneider für die kritische Betrachtung meiner Arbeit, seine stete Geduld bei der Beantwortung zahlreicher Fragen und seinen tiefgründigen Humor, der Histamin‐„Truppe“ mit Dr. David Schnell, Dr. Patrick Igel, Miroslaw Lopuch und Dr. Hendrik Preuss für manche Hilfestellung und Diskussion und vor allem Irena Brunskole für die gewissenhafte Korrektur meiner Arbeit, der DAAD‐Austauschstudentin Rince Wong (Vancouver, Kanada) sowie meinen Wahlpflicht‐ praktikantinnen Sissi Auburger und Marjeta Sema für ihre Beiträge und ihren Einsatz, meiner Bürokollegin Dr. Miriam Erdorf für unzählige anregende Diskussionen, lange unter‐ haltsame Laborabende, ihren Enthusiasmus und für die schöne gemeinsame Zeit auch außerhalb der Universität, meinen Bürokollegen Dr. Nina Lotter, Dr. Corina Matzdorf und Dr. Hesham Taha sowie meinen Laborkollegen Dr. Martin Göttle, Dr. Melanie Hübner, Dr. Kathrin Nickl und Sarah Sutor für zahlreiche wissenschaftliche und nicht‐wissenschaftliche Diskussionen und das angenehme Klima, Herrn Prof. Dr. Frieder Kees für seine wissenschaftlichen Ratschläge und die zeitweise Betreuung, für sein organisatorisches Geschick und die heiteren Unterhaltungen in den Tee‐ pausen, Herrn Prof. Dr. Jens Schlossmann für die Möglichkeit, auch nach dem Weggang von Herrn Prof. Dr. Seifert alle praktischen und theoretischen Arbeiten am Lehrstuhl abschließen zu können, Frau Dr. Katharina Wenzel‐Seifert für ihre vielen konstruktiven Ratschläge beim Erstellen meiner Präsentationen und die hilfreichen Diskussionen, Frau Gertraud Wilberg für ihre Unterstützung bei den Western‐Blots, für die Sf9‐Zellkultur und für ihre stete Hilfsbereitschaft sowie Frau Astrid Seefeld für die Hilfestellung bei den GTPase‐Assays, Frau Rita Prenzyna für ihr jederzeit offenes Ohr und die stets freundliche Unterstützung bei allen organisatorischen Angelegenheiten, allen Kollegen des Lehrstuhls für ihre Kollegialität, Hilfsbereitschaft und das gute Arbeits‐ klima, meinen Eltern, meinem Bruder und meiner Schwägerin für ihre stete Unterstützung und den Rückhalt, vor allem aber meinem Mann Tobias, auf den ich mich immer verlassen kann. Per aspera ad astra Seneca Contents I Contents ............................................................................................................ I List of Figures.................................................................................................... V List of Tables ................................................................................................... VII Abbreviations ................................................................................................ VIII Author`s declaration ....................................................................................... XII A. Introduction ........................................................1 A.1 General introduction to different classes of psychiatric drugs........................... 1 A.1.1 Distinction between depression and schizophrenia .......................................... 2 A.1.2 Examined antidepressant and antipsychotic drugs............................................ 4 A.1.2.1 Antidepressants................................................................................................ 5 A.1.2.1.1 Non-selective antidepressants .......................................................................... 5 A.1.2.1.1.1 Tricyclic antidepressants ................................................................................... 5 A.1.2.1.1.2 Tetracyclic antidepressants............................................................................... 7 A.1.2.1.2 Selective antidepressants.................................................................................. 8 A.1.2.1.2.1 Selective serotonin reuptake inhibitors............................................................. 8 A.1.2.1.2.2 Noradrenergic and specific serotonergic antidepressants ................................. 9 A.1.2.2 Mood stabilizers ............................................................................................... 9 A.1.2.3 Antipsychotics................................................................................................... 9 A.1.2.3.1 Typical antipsychotics ..................................................................................... 10 A.1.2.3.1.1 Phenothiazines ............................................................................................... 10 A.1.2.3.1.2 Thioxanthenes ................................................................................................ 11 A.1.2.3.1.3 Butyrophenones ............................................................................................. 11 A.1.2.3.2 Atypical antipsychotics ................................................................................... 12 A.1.3 Mechanisms of drug action ............................................................................. 13 A.1.4 Methods for therapeutic drug monitoring ...................................................... 17 A.2 General introduction to the family of histamine receptors ............................. 18 A.3 The endogenous neurotransmitter and local mediator histamine................... 20 A.4 G protein-cycle and examination methods...................................................... 23 A.5 Two-state model and constitutive activity ...................................................... 26 A.6 Sf9 cells and various other histamine receptor model systems ....................... 27 A.7 The histamine H2 receptor in the brain ........................................................... 30 A.8 Scope and objectives....................................................................................... 31 Contents II B. Materials and Methods .....................................36 B.1 Materials ........................................................................................................ 36 B.1.1 Equipment ...................................................................................................... 36 B.1.2 Chemicals, enzymes and antibodies................................................................ 37 B.1.3 Consumables................................................................................................... 43 B.1.4 Buffers ............................................................................................................ 43 B.2 Methods ......................................................................................................... 44 B.2.1 Solution protocols: handling of the antipsychotic and antidepressant ligands 44 B.2.2 Generation of recombinant baculoviruses, cell culture and membrane preparation..................................................................................................... 44 B.2.3 SDS-PAGE and immunoblot analysis ............................................................... 46 B.2.4 Radioligand binding assay............................................................................... 47 B.2.5 Steady-state GTPase assay.............................................................................. 49 B.2.6 Prediction of off-targets by Similarity Ensemble Approach.............................. 50 B.2.7 Construction of active and inactive state hHxR models with different compounds
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