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Radioligand Binding and Reporter Gene Assays for Histamine H3 and H4 Receptor Species Orthologs

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Radioligand Binding and Reporter Gene Assays for Histamine H3 and H4 Receptor Species Orthologs Radioligand binding and reporter gene assays for histamine H3 and H4 receptor species orthologs Dissertation Zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) der Fakultät für Chemie und Pharmazie der Universität Regensburg vorgelegt von Uwe Nordemann aus Ohrte 2013 Die vorliegende Arbeit entstand in der Zeit von Januar 2009 bis März 2013 unter der Leitung von Herrn Prof. Dr. A. Buschauer und Herrn Prof. Dr. G. Bernhardt am Institut für Pharmazie der Naturwissenschaftlichen Fakultät IV – Cheimie und Pharmazie – der Universität Regensburg. Das Promotionsgesuch wurde eingereicht im März 2013 Tag der mündlichen Prüfung: 04. April 2013 Prüfungsausschuss: Prof. Dr. D. Horinek (Vorsitzender) Prof. Dr. A. Buschauer (Erstgutachter) Prof. Dr. G. Bernhardt (Zweitgutachter) Prof. Dr. J. Wegener (Drittprüfer) für meine Eltern „Man sollte alles so einfach wie möglich sehen - aber auch nicht einfacher.“ Albert Einstein, 1879 - 1955 I Danksagungen An dieser Stelle möchte ich mich bedanken bei: Herrn Prof. Dr. A. Buschauer für die Gelegenheit, an diesem interessanten Projekt arbeiten zu dürfen, für seine wissenschaftlichen Anregungen und seine konstruktive Kritik bei der Durchsicht der Arbeit, Herrn Prof. Dr. G. Bernhardt für seine fachliche Anleitung, seine Anregungen bei experimentellen Problemen und seine konstruktive Kritik bei der Durchsicht der Arbeit, Herrn Prof. Dr. R. Seifert (Institut für Pharmakologie, Medizinische Hochschule Hannover) für die Bereitstellung der Vektoren pcDNA3.1(+)-SF-rH3R-His6 und pcDNA3.1(+)-SF-rH4R-His6 sowie diverser Histamin Rezeptor Liganden, Herrn Prof. Dr. H. Stark (Institut für Pharmazeutische Chemie, Goethe Universität Frankfurt am Main) für die Bereitstellung der H4 Rezeptor Liganden ST-1006 und ST-1012, Herrn Dr. D. Schnell für die Bereitstellung der HEK293-SF-hH3R-His6 und HEK293-SF-hH4R- His6 Zellen sowie der Vektoren pcDNA3.1(+)-SF-hH3R-His6 und pGEM-SF-mH4R-His6, Herrn Dr. P. Igel für die Bereitstellung des Radioliganden [3H]UR-PI294 und der Histamin Rezeptor Liganden UR-PI294 und UR-PI376 sowie für seine kompetente Hilfe bei experimentellen Problemen und pharmakologischen Fragestellungen, Herrn Dr. J. Mosandl für seine Hilfe beim Erlernen der Zellkultur und des Radioliganden- bindungsassays sowie beim theoretischen Einarbeiten in das Thema, Herrn Dr. P. Höcherl und Dr. M. Kühnle für die wertvollen Ratschläge bei der Durchführung der Transfektionen und die Hilfe beim Zytotoxizitätsassay, Herrn Dr. R. Geyer für die Bereitstellung der Cyanoguanidine und diverser anderer H4R Liganden, Frau B. Wenzl für ihre tatkräftige Unterstützung in der Zellkultur und der guten Zusammenarbeit während des Biochemie Praktikums, Frau M. Beer-Krön für ihre tatkräftige Unterstützung in der Zellkultur und die vielen Süßigkeiten im Büro, II Herrn P. Richthammer für seine Hilfsbereitschaft und Kompetenz bei allen technischen Problemen und seine stets norddeutsche Begrüßung, Frau U. Hasselmann und Frau K. Reindl für ihre freundliche Unterstützung bei allen organisatorischen Dingen, Herrn Dr. M. Keller, T. Holzammer und D. Wifling für die vielen fachlichen Gespräche, meinen aktuellen und ehemaligen Bürokollegen Frau M. Kaske, N. Kagermeier, Herrn M. Rothenhöfer, S. Huber und J. Felixberger für die angenehme und amüsante Atmosphäre und die gute Zusammenarbeit, Frau S. Dukorn und allen anderen Forschungspraktikanten / -innen für ihre engagierte Mitarbeit im Labor, allen ehemaligen und aktuellen Doktoranden / innen, Diplomanden / -innen und Masteranden / -innen für eine tolle Zeit am und außerhalb des Lehrstuhls, allen aktuellen und ehemaligen Mitarbeitern des Lehrstuhls für eine sehr gute Kollegialität, Arbeitsatmosphäre und Zusammenarbeit, der Deutschen Forschungsgemeinschaft für die finanzielle Förderung im Rahmen des Graduiertenkollegs 760 sowie der EU für die Unterstützung im Rahmen des COST Projektes BM0806, und insbesondere meinen Eltern, meinen Geschwistern und natürlich meiner Freundin Doris für ihren Rückhalt, ihre Unterstützung und Hilfe in jeglicher Art und Weise. III Poster presentations Nordemann U.; Schnell D.; Bernhardt G.; Seifert R.; Buschauer A.: Reporter gene assay for th the investigation of human, murine and rat histamine H4 receptor ligands. 6 Summer School Medicinal Chemistry, Regensburg, Germany, September 26 – 28, 2012 Geyer R.; Nordemann U.; Baumeister P.; Bernhardt G.; Buschauer A.: trans-(+)-(1S,3S)-UR- RG98: Synthesis, absolute configuration and pharmacological characterization of a highly nd potent and selective histamine H4 receptor agonist. EFMC-ISMC 2012, 22 International Symposium on Medicinal Chemistry, Berlin, Germany, September 02 – 06, 2012 Nordemann U.; Schnell D.; Bernhardt G.; Seifert R.; Buschauer A.: Gene reporter assay for the investigation of human and murine histamine H4 receptor ligands. Joint meeting of the Austrian and German Pharmaceutical Societies, Innsbruck, Austria, September 20 – 23, 2011 Baumeister P.; Nordemann U.; Buschauer A.: 2-Arylbenzimidazoles as potent human H4 receptor agonists. Frontiers in Medicinal Chemistry, Saarbrücken, Germany, March 20 – 23, 2011 Nordemann U.; Mosandl J.; Schnell D.; Bernhardt G.; Buschauer A.: Development of cell- th based binding and functional assays for the human histamine H3 and H4 receptor. 5 Summer School Medicinal Chemistry, Regensburg, Germany, September 13 – 15, 2010 Erdmann D.; Mosandl J.; Nordemann U.; Bernhardt G.; Wolfbeis O.S.; Seifert R.; Buschauer A.: Pharmacological activity and selectivity of fluorescent histamine H3 receptor ligands. Annual meeting of the German Pharmaceutical Society, Jena, Germany, September 28 – October 1, 2009 V Contents Chapter 1 General introduction ....................................................................................... 1 1.1 G-protein coupled receptors (GPCRs) .............................................................. 2 1.1.1 GPCRs as drug target ....................................................................................... 2 1.1.2 Structure and classification ............................................................................... 2 1.1.3 Advances in X-ray crystallography for GPCRs ................................................. 5 1.1.4 Signal transduction ............................................................................................ 7 1.1.4.1 G-protein mediated signal transduction ............................................................ 7 1.1.4.2 β-Arrestin dependent signaling ......................................................................... 8 1.1.4.3 Models of GPCR signaling, ligand classification and functional selectivity ..... 10 1.2 Histamine and the histamine receptor family .................................................. 12 1.2.1 The biogenic amine histamine ........................................................................ 12 1.2.2 Histamine receptors and their ligands ............................................................. 15 1.2.2.1 The histamine H1 receptor ............................................................................... 15 1.2.2.2 The histamine H2 receptor ............................................................................... 17 1.2.2.3 The histamine H3 receptor ............................................................................... 19 1.2.2.4 The histamine H4 receptor ............................................................................... 22 1.3 References ...................................................................................................... 26 Chapter 2 Scope and objectives ................................................................................... 39 Chapter 3 Development of radioligand binding assays for human and mouse histamine H4 receptors ................................................................................. 41 3.1 Radioligand binding assay for the human histamine H4 receptor .................... 42 3.1.1 Introduction ..................................................................................................... 42 3.1.2 Materials and Methods .................................................................................... 44 3.1.2.1 Cell culture ...................................................................................................... 44 3.1.2.2 Chemosensitivity assay ................................................................................... 44 3.1.2.3 H4 receptor ligands .......................................................................................... 45 3.1.2.4 Whole cell radioligand binding assay .............................................................. 46 3.1.3 Results and discussion ................................................................................... 49 3.1.3.1 Effect of Geneticin (G418) on HEK293T cells ................................................. 49 3.1.3.2 Saturation binding assay ................................................................................. 49 3.1.3.3 Competition binding assay .............................................................................. 50 3.2 Radioligand binding assay for the mouse histamine H4 receptor .................... 56 3.2.1 Introduction ..................................................................................................... 56 VI 3.2.2 Materials and methods .................................................................................... 57 3.2.2.1 Subcloning of the pcDNA3.1(+)SF-mH4R-His6 vector ..................................... 57 3.2.2.1.1 Restriction
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