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Molecular Tools for G-Protein Coupled Receptors: Synthesis

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Molecular Tools for G-Protein Coupled Receptors: Synthesis Molecular Tools for G-Protein Coupled Receptors: Synthesis, Pharmacological Characterization and [3H]-Labeling of Subtype-selective Ligands for Histamine H4 and NPY Y2 Receptors Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) an der Fakultät für Chemie und Pharmazie der Universität Regensburg vorgelegt von Paul Baumeister aus Zinzenzell 2014 Die vorliegende Arbeit entstand in der Zeit von April 2010 bis April 2014 unter der Anleitung von Herrn Prof. Dr. Armin Buschauer am Institut für Pharmazie der Naturwissenschaftlichen Fakultät IV – Chemie und Pharmazie – der Universität Regensburg. Das Promotionsgesuch wurde eingereicht im Juni 2014. Tag der mündlichen Prüfung: 18.07.2014 Prüfungsausschuss: Prof. Dr. J. Heilmann (Vorsitzender) Prof. Dr. A. Buschauer (Erstgutachter) Prof. Dr. S. Elz (Zweitgutachter) Prof. Dr. J. Wegener (Drittprüfer) „If you don’t turn your life into a story, you just become a part of someone else’s story.“ Terry Pratchett I Danksagung An dieser Stelle möchte mich ganz herzlich bei allen bedanken, die zum Gelingen dieser Arbeit beigetragen haben und mich während der Promotionszeit begleitet haben. Besonders möchte ich danken: Meinem Doktorvater Herrn Prof. Dr. Armin Buschauer für das Vertrauen und die Möglichkeit dieses interessante und herausfordernde Projekt zu verwirklichen, seine wissenschaftlichen Anregungen, für die mir gewährte forscherische Freiheit, seine konstruktive Kritik bei der Durchsicht der Arbeit, sein stets offenes Ohr, sowie die Mentorenschaft in der Emil-Fischer-Graduiertenschule; Herrn Prof. Dr. Günther Bernhardt für seine stete Hilfsbereitschaft und sein Interesse am Fortschritt der Arbeit, sein Fachwissen, die Durchsicht der Arbeit, die Co-Mentorenschaft in der Emil-Fischer- Graduiertenschule, sowie für hervorragenden Sommerfeste; Herrn Prof. Dr. Sigurd Elz für die Erstellung des Zweitgutachtens und die Teilnahme an der mündlichen Prüfung; Herrn Prof. Dr. Joachim Wegener für die Bereitschaft als Drittprüfer an der mündlichen Prüfung teilzunehmen und die Co-Mentorenschaft in der Emil-Fischer-Graduiertenschule; Herrn Prof. Dr. Jörg Heilmann für die Teilnahme als Vorsitzender in der mündlichen Prüfung; Herrn Dr. Max Keller für seine fachliche und soziale Kompetenz, die hervorragende Zusammenarbeit, aufmunternde Worte, seine Motivation, die Bereitstellung von Synthesebausteinen und die gemütlichen Abende bei selbstgemachtem Wein; Herrn Dr. Patrick Igel und Herrn Dr. Roland Geyer für die ausführliche Einführung in die Histamin- Welt, die fachlichen Tipps und die Bereitstellung von Synthesebausteinen; Herrn Dr. Nikola Pluym für die ausführliche Einführung in die NPY-Welt, die fachlichen Diskussionen, seine soziale Kompetenz, die Bereitstellung von Synthesebausteinen und die Einführung in die Welt der Radioligandsynthese; Herrn Dr. Thilo Spruss, Herrn Franz Wiesenmayer und Frau Petra Pistor für die Betreuung und Unterstützung bei der Durchführung der Tierversuche, sowie für das Anfertigen der Kryoschnitte von Gewebeproben und deren histologischen Färbung; Herrn Dr. Uwe Nordemann für die Durchführung der HEK293 Zellexperimente mit [3H]JNJ7777120 und die Einweisung in die Welt der Radioligandsynthese; Frau Nicole Kagermeier für die fachlichen Diskussionen und die Durchführung der HEK293 Zellexperimente mit [3H]UR-DE257; Frau Maria Beer‐Krön, Frau Dita Fritsch, Frau Susanne Bollwein, Frau Elvira Schreiber und Frau Brigitte Wenzl für die tatkräftige Unterstützung bei der Durchführung vieler Assays, HPLC-Läufe und der Zellkultivierung; Herrn Peter Richthammer für die zahlreichen netten Gespräche, seine stete Hilfsbereitschaft und Kompetenz bei allen technischen Herausforderungen und für die gute Zusammenarbeit bei der Durchführung der verschiedenen Praktika; Frau Uta Hasselmann, Frau Karin Reindl und Frau Silvia Heinrich für die stets freundliche Unterstützung bei allen organisatorischen Angelegenheiten; II Frau Edith Bartole, Frau Shiwen Xue, Herrn Josef Auburger, Herrn Michael Schupfner und Herrn Markus Friedrich für die Durchführung von Versuche im Rahmen Ihrer Praktika; Allen Laborkollegen, allen Mitgliedern der Histamin-Gruppe und der NPY-Gruppe für die angenehme, inspirierenden und gelegentlich auch amüsanten Atmosphäre und die sehr gute Zusammenarbeit; Frau Edith Bartole und Frau Sabrina Biselli für die gute Zusammenarbeit im Rahmen der Betreuung Ihrer Masterarbeiten; Allen Mitarbeitern der analytischen Abteilung der Universität Regensburg für die Aufnahme und Hilfestellung bei der Interpretation der NMR- und Massenspektren. Ein besonderer Dank geht hierbei an Herrn Fritz Kastner und Herrn Josef Kiermaier für die hilfreichen Diskussionen und die Ermittlung zahlreicher analytischer Daten; Allen Mitgliedern der Arminia Buschauer für die tolle Zeit am Lehrstuhl, die stets gute Kollegialität, Arbeitsatmosphäre und Zusammenarbeit; Frau Dr. Stefanie Bauer, Herrn Dr. Roland Geyer, Herrn Stefan Huber, Frau Nicole Kagermeier, Herrn Dr. Nikola Pluym, Frau Edith Bartole, Herrn Steffen Pockes und Frau Maria Beer-Kroen für die vielen netten Gespräche und schöne Zeit; Den Mitarbeitern der FAU Erlangen, Herrn Prof. Dr. Peter Gmeiner, Herrn Prof. Dr. Markus Heinrich, Frau Dr. Nuska Tschammer, Herrn Dr. Viachaslau Bernat, Herrn Dr. Harald Hübner und Michael Fürst für die gute Zusammenarbeit; Herrn Prof. Dr. Oliver Reiser und Dr. Julian Bodensteiner für die gute Zusammenarbeit; Der Deutschen Forschungsgemeinschaft für die finanzielle Förderung im Rahmen des Graduiertenkollegs GRK 760; Special thanks to my coworkers and friends Jianfei Wan and Xueke She for the great opportunity to visit their homeland China, all the hospitality, patience and unforgettable impressions. 谢谢! 干杯! Meinen Freunden und dem Trimmverein Regensburg, auf die man sich immer verlassen konnte, wenn es darauf ankam. ‚Reich sind nur die, die wahre Freunde haben‘ (Thomas Fuller); Den Herren Dr. Daniel Bücherl, Petr Jirásek und Michel Leonhardt für die allmorgendliche Frühstücksrunde, sowie die moralische und fachliche Unterstützung; Zuletzt all denjenigen, die das Leben lebenswert machen und mehr als nur Dank verdienen: meinen Eltern, meinen Geschwistern und meiner Freundin Marina. Ihnen ist die vorliegende Arbeit gewidmet. III Publications (published results prior to the submission of this thesis): (1) Baumeister, P., Erdmann, D., Biselli, S., Kagermeier, N., Bernhardt, G., Buschauer, A.: [3H]UR- DE257: A Selective and Highly Potent Tritium-Labeled Squaramide-type Histamine H2 Receptor Antagonist. ChemMedChem 2014, in preparation. (2) Geyer, R., Kaske, M., Baumeister, P., Buschauer, A.: Synthesis and Functional Characterization of Imbutamine Analogs as Histamine H3 and H4 Receptor Ligands. Arch. Pharm. Chem. Life Sci. 2014, 347, 77–88. (3) Pluym, N., Baumeister, P., Keller, M., Bernhardt, G., Buschauer, A.: [3H]UR-PLN196: A Selective Nonpeptide Radioligand and Insurmountable Antagonist for the Neuropeptide Y Y2 Receptor. ChemMedChem Comm. 2013, 8, 587-593. (4) Bodensteiner, J., Baumeister, P., Geyer, R., Buschauer, A., Reiser, O.: Synthesis and Pharmacological Characterization of New Tetrahydrofuran Based Compounds as Conformationally Constrained Histamine Receptor Ligands. Org. Biomol. Chem. 2013, 11, 4040-4055. (5) Bernat, V., Heinrich, M., Baumeister, P., Buschauer, A., Tschammer, N.: Synthesis and Application of the First Radioligand Targeting the Allosteric Binding Pocket of Chemokine Receptor CXCR3. ChemMedChem 2012, 7 (8), 1481-1489. Short Lecture: Baumeister, P.: The First Selective Tritium-labeled Nonpeptide Radioligands for the NPY Y2 Receptor. Christmas Colloquium 2012 of the Department of Organic Chemistry, University of Regensburg, 19.12.2012. Poster Presentations: 03/2013 Annual Meeting of the GDCh, Fachgruppe Medizinische Chemie, Frontiers in Medicinal Chemistry, München. Baumeister, P., Pluym, N., Keller, M., Bernhardt, G., Buschauer, A.: Subtype-selective Nonpeptide NPY Y2 Receptor Radioligands. 09/2012 XXIInd International Symposium on Medicinal Chemistry (ISMC), Berlin. Baumeister, P., Erdmann, D., Bernhardt, G., Buschauer, A.: [3H]UR-DE257: A New Tritium-labeled Histamine H2 Receptor Antagonist. Bernat, V., Heinrich, M., Baumeister, P., Buschauer, A., Tschammer, N.: Synthesis and Application of the First Small-Molecule Radioligand Targeting the Human Chemokine Receptor CXCR3. Best Poster Award IV 09/2012 6th Summer School in Medicinal Chemistry, Regensburg. Geyer, R., Nordemann, U., Baumeister, P., Bernhardt, G., Buschauer, A.: trans‐(+)‐(1S,3S)‐UR‐RG98: Synthesis, Absolute Configuration and Pharmacological Characterization of a Highly Potent and Selective Histamine H4 Receptor Agonist. 03/2011 Annual Meeting of the GDCh, Fachgruppe Medizinische Chemie, Frontiers in Medicinal Chemistry, Saarbrücken. Baumeister, P., Buschauer, A.: 2-Arylbenzimidazoles as Potent Human Histamine H4 Receptor Agonists. Professional Training: 04/2013 Fortbildung für Projektleiter und Beauftragter für Biologische Sicherheit (§15 und 17 Gentechniksicherheitsverordnung). Regensburg, Germany. 06/2010 Umgang mit offenen radioaktiven Stoffen. Regensburg, Germany. 03/2010 – 03/2012 Member of the Research Training Group (Graduiertenkolleg 760) “Medicinal Chemistry: Molecular Recognition – Ligand Receptor Interactions” of the German Research Foundation. Regensburg, Germany. 06/2012 – 04/2014 Member of the Emil Fischer Graduate School of Pharmaceutical Sciences and Molecular Medicine. Regensburg, Erlangen, Germany. V Contents 1 Introduction ..........................................................................................................................
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