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Pharmacological Tools for the NPY Receptors: [35S]Gtpγs Binding Assays, Luciferase Gene Reporter Assays and Labeled Peptides

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Pharmacological Tools for the NPY Receptors: [35S]Gtpγs Binding Assays, Luciferase Gene Reporter Assays and Labeled Peptides Pharmacological tools for the NPY receptors: [35S]GTPγS binding assays, luciferase gene reporter assays and labeled peptides Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) an der Fakultät für Chemie und Pharmazie der Universität Regensburg vorgelegt von Stefanie Dukorn aus Straubing 2017 Die vorliegende Arbeit entstand in der Zeit von Januar 2013 bis März 2017 unter der Leitung 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 März 2017. Tag der mündlichen Prüfung: 21. April 2017 Prüfungsausschuss: Prof. Dr. S. Elz (Vorsitzender) Prof. Dr. A. Buschauer (Erstgutachter) Prof. Dr. G. Bernhardt (Zweitgutachter) Prof. Dr. J. Wegener (Drittprüfer) Danksagungen An dieser Stelle möchte ich mich herzlich bedanken bei: Herrn Prof. Dr. Armin Buschauer, dass ich die Möglichkeit für dieses vielseitige Projekt erhalten habe, seine wissenschaftlichen Anregungen sowie Förderungen und seine konstruktive Kritik bei der Durchsicht der Arbeit, Herrn Prof. Dr. Günther Bernhardt für seine Hilfsbereitschaft und sein Interesse am Fortschritt der Arbeit, sein Fachwissen und die Durchsicht der Arbeit, Herrn Prof. Dr. Oliver Zerbe und Dr. Jacopo Marino für die Kooperation zu Beginn meiner Arbeit, mit Unterstützung von Dr. Oliver Biehlmaier der Imaging Core Facility in Basel, Herrn Dr. Paul Baumeister, der zu Beginn und im weiteren Verlauf meiner Doktorarbeit immer ein offenes Ohr für jegliche Angelegenheiten hatte und entsprechend seinen fachlichen Ratschlägen, Herrn Dr. Max Keller für die wertvollen fachlichen Tipps, die hervorragende Zusammenarbeit, das Bereitstellen von verschiedenen Substanzen, sowie für die fachlichen Diskussionen und Ratschläge, Herrn Dr. Kilian Kuhn für die sehr gute Zusammenarbeit, NPY hat uns beide während dieser Zeit begleitet und entsprechend beschäftigt, Herrn Timo Littmann für die Durchführung der Arrestin Assays, Frau Prof. Dr. Chiara Cabrele für die Bereitstellung der Peptide, Frau Dr. Birgit Kraus für die Unterstützung bei der Fluoreszenzmikroskopie, Frau Dr. Andrea Bleckmann für die Bereitstellung des Konfokalmikroskops, Frau Elvira Schreiber für die Durchführung der zahlreichen pharmakologischen Bestimmungen am FACS und Durchführung von Calcium Assays, Frau Brigitte Wenzl für die Unterstützung v.a. zu Beginn meiner praktischen Laborarbeit und für die gute Zusammenarbeit während der Praktikumsbetreuung, Frau Susanne Bollwein und Frau Dita Fritsch für die Durchführung von HPLC-Läufen und Experimenten, Frau Maria Beer- Krön für ihre Unterstützung und der Durchführung von [35S]GTPγS Assays und Radioligand-Bindungsexperimenten, meiner Praktikantin Lisa Schindler für die Durchführung von Calcium Assays, Herrn Josef Kiermaier und Herrn Wolfgang Söllner für die Anfertigung der MS- Untersuchungen, the office 14.2.08 for the great collegiality, especially Timo Littmann, Dr. Nicole Plank, Andrea Pegoli and Frauke Antoni, meinem ehemaligen Kollegen Herrn Dr. Uwe Nordemann für die Betreuung während meines Forschungspraktikums, Frau Karin Reindl, Frau Uta Hasselmann, Frau Silvia Heinrich und Herrn Peter Richthammer für die Unterstützung bei technischen und organisatorischen Angelegenheiten, allen Mitgliedern des Lehrstuhls für ihre Kollegialität, Hilfsbereitschaft und ein gutes Arbeitsklima, meinen Freunden für die gemeinsame Zeit und das Interesse am Fortgang meiner Arbeit, „Freundschaft fließt aus vielen Quellen, am reinsten aus Vertrauen und Respekt.“ Zuletzt all denjenigen, die mehr als nur Dank verdienen: Meiner Familie. Ihnen ist die vorliegende Arbeit gewidmet. Publications and Poster Presentations Publications (published results prior to the submission of the thesis): Kuhn K., Ertl T., Dukorn S., Keller M., Bernhardt G., Reiser O., Buschauer A., High Affinity Agonists of the Neuropeptide Y (NPY) Y4 Receptor Derived from the C-terminal Pentapeptide of Human Pancreatic Polypeptide (hPP): Synthesis, Stereochemical Discrimination and Radiolabeling, Journal of Medicinal Chemistry 2016, 59 (13), S. 6045-6058 Keller M., Weiss S., Hutzler C., Kuhn K., Mollereau C., Dukorn S., Schindler L., Bernhardt G., König B., Buschauer A., N(omega)-carbamoylation of the argininamide moiety: an avenue to insurmountable NPY Y1 receptor antagonists and a radiolabeled selective high affinity molecular tool ([3H]UR-MK299) with extended residence time, Journal of Medicinal Chemistry 2015, 58 (22), S. 8834-8849 Poster Presentations: Dukorn, S., Keller, M., Bernhardt, G., Buschauer, A., Investigations on the effect of sodium 4 17,30 on hY4R binding using fluorescent and radiolabelled [Lys ,Nle ]hPP as new molecular tools, 8th Summer School Medicinal Chemistry, Regensburg, September 2016. Dukorn S., Keller M., Kuhn K., Cabrele C., Bernhardt G., Buschauer A., Molecular tools for 4 17,30 th the NPY Y4 receptor: Fluorescence- and radiolabelled [Lys ,Nle ]hPP, 11 International NPY-PYY-PP Meeting, Leipzig, August 2015. Dukorn S., Marino J., Zerbe O., Bernhardt G. and Buschauer A., [3H]Propionyl-K4hPP: A novel radioligand for the neuropeptide Y (NPY) Y4 receptor, 7th Summer School Medicinal Chemistry, Regensburg, September 2014. Dukorn, S., Marino, J., Zerbe, O., Bernhardt, G., Buschauer, A., A valuable tool for the NPY 3 4 Y4 receptor: [ H]Propionyl - K hPP, Annual Meeting “Frontiers in Medicinal Chemistry”, Tübingen, March 2014. I Contents Abbreviations .................................................................................................................... IV 1 Introduction ................................................................................................... 1 1.1 Neuropeptide Y ........................................................................................... 2 1.2 NPY receptors and their ligands ................................................................. 2 1.2.1 The NPY Y1, Y2 and Y5 receptors and their ligands ............................................. 4 1.2.2 The NPY Y4 receptor and its ligands ................................................................... 8 1.3 Sodium sensitivity of the NPY receptors ................................................... 10 1.4 Tritium- and fluorescence-labeled NPY receptor ligands .......................... 11 1.4.1 Tritiated radioligands ......................................................................................... 11 1.4.2 Fluorescent ligands for cellular investigations ................................................... 11 1.5 References ............................................................................................... 12 2 Scope and objectives ............................................................................... 19 35 3 Development of a [ S]GTPγS binding assay for hY2 and hY4 receptors in Sf9 membranes .................................................................. 21 3.1 Introduction ............................................................................................... 22 3.2 Material and methods ............................................................................... 23 3.2.1 Materials ........................................................................................................... 23 3.2.2 Cell culture, generation of recombinant baculoviruses, Sf9 cell membrane preparation ........................................................................................................ 24 35 3.2.3 [ S]GTPγS binding assay at the hY2R and the hY4R ........................................ 24 3.2.4 Radioligand binding at hY4R Sf9 membranes .................................................... 25 3.3 Results and discussion .......................................................................... 25 35 3.3.1 [ S]GTPγS binding assay at the hY2R .............................................................. 25 35 3.3.2 [ S]GTPγS binding assay at the hY4R .............................................................. 27 3.4 Summary and conclusion ......................................................................... 31 3.5 References ............................................................................................... 31 4 Development of luminescence based reporter gene assays for the human neuropeptide Y2 and Y4 receptor ............................. 33 4.1 Introduction ............................................................................................... 34 4.2 Materials and methods ............................................................................. 36 4.2.1 Stable transfection of HEK293T-hY2-CRE Luc and HEK293T-hY4-CRE Luc cells with the pGL4.29[luc2P/CRE/Hygro] vector ............................................... 36 4.2.2 Cell culture ........................................................................................................ 37 4.2.3 Saturation binding on HEK293T-CRE-Luc hY2R and HEK293T-CRE-Luc hY4R cells.......................................................................................................... 37 II 4.2.4 Luciferase reporter gene assay ......................................................................... 38 4.2.4.1 Preparation of stock solutions and dilution series ..................................................... 38 4.2.4.2 Preparation of the cells and determination of bioluminescence .................................. 38 4.2.4.3 Effect of the solvent on luciferase activity ................................................................ 39 4.2.4.4 Determination
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