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Synthesis and Pharmacological Characterization of New Histamine Synthesis and pharmacological characterization of new histamine H1-/H4-receptor ligands derived from the atypical antipsychotic drug Clozapine Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) der Naturwissenschaftlichen Fakultät IV – Chemie und Pharmazie – der Universität Regensburg vorgelegt von Susanne Gobleder aus Eichstätt 2014 Die vorliegende Arbeit entstand in der Zeit von Juli 2010 bis Mai 2014 unter der Leitung von Frau PD Dr. Andrea Straßer und Herrn Prof. Dr. Sigurd Elz am Institut für Pharmazie der Naturwissenschaftlichen Fakultät IV - Chemie und Pharmazie - der Universität Regensburg. Das Promotionsgesuch wurde eingereicht im Mai 2014. Tag der mündlichen Prüfung: 23. Mai 2014 Prüfungsausschuss: Prof. Dr. A. Buschauer (Vorsitzender) PD Dr. A. Straßer (Erstgutachterin) Prof. Dr. S. Elz (Zweitgutachter) Prof. Dr. J. Heilmann (Drittprüfer) Author’s Declaration The author declares that the work presented in this thesis was written by none other than herself. Apart from were indicated, all work was performed or supervised by the author. Molecular dynamics simulations described in Chapter 4.4.1.2 and Figure 4.5 were performed by PD Dr. A. Straßer and Dr. H.-J. Wittmann (Department of Pharmaceutical / Medicinal Chemistry II, University of Regensburg, Germany; Faculty of Chemistry and Pharmacy, University of Regensburg, Germany). Competition binding assays at dopamine, serotonin and muscarine receptors described in Chapter 4.4.3 were performed by Prof. Dr. P. Gmeiner, Dr. H. Hübner and Coworkers (Department of Pharmaceutical Chemistry, Friedrich Alexander University Erlangen – Nürnberg, Germany). Danksagungen An dieser Stelle möchte ich mich bedanken bei: Frau PD Dr. Andrea Straßer für die wissenschaftlichen Anregungen und die konstruktive Kritik bei der Durchsicht dieser Arbeit, für die Erstellung des Erstgutachtens sowie für die strukturierte, gewissenhafte und zielorientierte Betreuung während der gesamten Promotionszeit, Herrn Prof. Dr. Sigurd Elz für die Vergabe des interessanten und herausfordernden Promotionsthemas, für seine geduldige Hilfestellung bei der Interpretation der organpharmakologischen Daten am Meerschweinchen-Ileum und für die Erstellung des Zweitgutachtens, Herrn Prof. Dr. Jörg Heilmann für seine Bereitschaft, das Amt des Drittprüfers zu übernehmen, Herrn Prof. Dr. Armin Buschauer für die Möglichkeit zur Teilnahme an den Lehrstuhlseminaren seines Arbeitskreises sowie zur Durchführung der pharmakologischen Arbeiten an seinem Lehrstuhl und dafür, dass er sich bereit erklärt hat, den Vorsitz der Prüfungskommission zu übernehmen, Herrn Prof. Dr. Jens Schlossmann für die Zurverfügungstellung von Laborräumen und -verbrauchsmaterialien zur Durchführung der Radioligand-Bindungsassays an seinem Lehrstuhl, Herrn Dr. Hans-Joachim Wittmann für die Erstellung der Molecular Dynamics Simulationen am Histamin H1- und H4-Rezeptor, Frau Maria Beer-Krön für die Bereitstellung der Sf9-Zellen, ihre außerordentliche Hilfsbereitschaft bei der Membranpräparation sowie für ihre Unterstützung bei der Durchführung der steady-state [33P]GTPase- und [35S]GTPγS Assays, Frau Christine Braun und Frau Kerstin Röhrl für die zuverlässige Durchführung der organpharmakologischen Testungen am Meerschweinchen-Ileum, Frau Gertraud Wilberg für die Bereitstellung der Sf9-Zellen sowie für ihre Hilfsbereitschaft in allen Bereichen der pharmakologischen Labortätigkeiten, Frau Uta Hasselmann für ihre tatkräftige Unterstützung bei organisatorischen Problemen aller Art und für ihre ansteckende gute Laune, allen Mitarbeitern der analytischen Abteilungen der Fakultät für die Aufnahme der NMR- und Massenspektren sowie für die Durchführung der Elementaranalysen, allen Mitgliedern der Lehrstühle Pharmazeutische Chemie I und Pharmazeutische Chemie II für das angenehme Arbeitsklima, die kollegiale Zusammenarbeit und die stetige Hilfsbereitschaft bei chemischen Problemstellungen (hierbei gilt der Dank insbesondere Herrn Dr. Herwig Pongratz und Herrn Dr. Andreas Sellmer), meinen Kollegen Frau Bernadette Streifinger und Herrn Michel Leonhard für die geduldige Hilfe bei der Formatierung dieser Arbeit, meinem Kollegen Herrn Thomas Dang-Lieu für die Unterstützung bei Netzwerk- und Computerproblemen, Frau Franziska Naporra für die engagierte Mitarbeit im Labor im Rahmen ihres Forschungspraktikums, meinem Laborkollegen Herrn Steffen Pockes für eine fabelhafte musikalische Untermalung der gemeinsamen Laborzeit (möge sich die Discokugel immer drehen) sowie für die gute Freundschaft während der Promotion, meinen Kolleginnen in der Marien Apotheke Schierling, die mir durch ihr herzliches Betriebsklima eine angenehme Abwechslung zum Laboralltag geboten haben, meinen Eltern für ihre liebevolle Fürsorge, ihre Ermutigung und ihre Unterstützung während des Studiums und der Promotion, und vor allem meinem Freund Tommy für seine Geduld, sein Verständnis und seinen bedingungslosen Rückhalt in allen Lebenslagen. Scientific presentations . EFMC-ISMC 21st International Symposium on Medicinal Chemistry, Brussels (Belgium), 05. – 09.09.2010 Poster presentation. E. Wagner, S. Gobleder and A. Straßer. “Synthesis, pharmacological characterization and molecular modelling of dual Histamine H1-/H4-receptor antagonists.” . 5th Summer School “Medicinal Chemistry”, Regensburg (Germany), 13. – 15.09.2010 Poster presentation. E. Wagner, S. Gobleder and A. Straßer. “Synthesis, pharmacological characterization and molecular modelling of dual Histamine H1-/H4-receptor antagonists.” . Joint Meeting of the Austrian and German Pharmaceutical Societies, Innsbruck (Austria), 20. – 23.09.2011 Poster presentation. S. Gobleder, S. Elz and A. Straßer. “Synthesis and pharmacology of Clozapine-derived Histamine H1-/H4-receptor ligands.” . 6th Summer School “Medicinal Chemistry”, Regensburg (Germany), 26. – 28.09.2012 Oral poster presentation. S. Gobleder, S. Elz and A. Straßer. “New Clozapine derived Histamine H1-/H4-receptor ligands as possible treatment of type-I- allergic diseases.” . Annual meeting of the German Pharmaceutical Society, Greifswald (Germany), 10. – 13.10.2012 Poster presentation. S. Gobleder, H.-J. Wittmann, S. Elz and A. Straßer. “New Clozapine derived Histamine H1-/H4-receptor ligands as possible treatment of type-I-allergic diseases.” . Annual meeting of the German Pharmaceutical Society, Freiburg (Germany), 09. – 11.10.2013 Poster presentation. S. Gobleder, H.-J. Wittmann, S. Elz and A. Straßer. “New Clozapine derived dimeric Histamine H1-/H4-receptor ligands and their pharmacological characterization.” Contents ___________________________________________________________________ CONTENTS 1. INTRODUCTION _________________________________________________ 2 1.1. The G-Protein coupled receptors (GPCRs) ______________________________________ 2 1.1.1. Structure and classification of GPCRs _______________________________________ 2 1.1.2. GPCRs on a molecular level _______________________________________________ 3 1.1.3. The G-protein cycle ______________________________________________________ 4 1.1.4. Signal transduction pathways of GPCRs _____________________________________ 6 1.1.5. Receptor activation and ligand classification __________________________________ 8 1.1.6. GPCR oligomerization and dimerization: bivalent ligands and their interaction with the receptors _____________________________________________________________ 10 1.2. Histamine and the histamine receptor family ___________________________________ 12 1.2.1. The histamine H1 receptor _______________________________________________ 13 1.2.2. The histamine H2 receptor _______________________________________________ 17 1.2.3. The histamine H3 receptor _______________________________________________ 19 1.2.4. The histamine H4 receptor _______________________________________________ 23 1.3. Antipsychotic drugs __________________________________________________________ 26 1.3.1. Classification __________________________________________________________ 26 1.3.2. Clozapine and its interaction with multiple molecular targets (“dirty drug” problem) ___ 28 1.4. References ___________________________________________________________________ 30 2. SCOPE AND OBJECTIVES _________________________________ 46 References ___________________________________________________________________ 49 3. CHEMICAL SECTION ______________________________________ 52 3.1. Ligand design related to VUF 6884 (Smits et al., 2006) __________________________ 52 3.2. Synthesis of the “open” phenylbenzamidines: opening up the rigid aromatic ring system in the center of the molecule __________________________________________ 53 3.2.1. VUF 6884 reduced to the core: (E)-N-(2-aminoethyl)-N'-phenylbenzamidine derivatives 53 3.2.2. “Open” VUF 6884 derivatives with modified substitution pattern: detecting the influence of kind and position of the substituents ________________________________________ 54 3.2.3. Acylated open VUF 6884 derivatives: an attempt to increase the hH4R affinity _______ 58 3.3. Synthesis of the closed VUF 6884 derivatives: return to a rigid aromatic ring system in the center of the molecule __________________________________________________ 61 Contents ___________________________________________________________________ 3.3.1. “Ring-closed” VUF 6884 derivatives with modified substitution pattern: determining the key role of the closed central heterocycle in synergy with the substitution pattern ________ 62 3.3.2. “Closed” VUF 6884 derivatives with a modified piperazine moiety: exchanging N- methylpiperazine
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