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Highly Potent, Selective Acylguanidine-Type Histamine H2

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Highly Potent, Selective Acylguanidine-Type Histamine H2 Highly Potent, Selective Acylguanidine-Type Histamine H2 Receptor Agonists: Synthesis and Structure-Activity Relationships Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer.nat.) der Naturwissenschaftlichen Fakultät IV - Chemie und Pharmazie – der Universität Regensburg vorgelegt von Anja Kraus aus Neumarkt i. d. OPf. 2007 Die vorliegende Arbeit entstand in der Zeit von April 2004 bis November 2007 unter der Leitung von Herrn Prof. Dr. A. Buschauer am Institut für Pharmazie der Naturwissenschaftlichen Fakultät IV – Chemie und Pharmazie – der Universität Regensburg. Das Promotionsgesuch wurde eingereicht im November 2007. Tag der mündlichen Prüfung: 14. Dezember 2007 Prüfungsausschuß: Prof. Dr. A. Göpferich (Vorsitzender) Prof. Dr. A. Buschauer (Erstgutachter) Prof. Dr. S. Elz (Zweitgutachter) Prof. Dr. H.-A. Wagenknecht (Prüfer) Es irrt der Mensch, solang´ er strebt. Johann Wolfgang von Goethe, Faust I Danksagung An dieser Stelle möchte ich mich bedanken bei: Herrn Prof. Dr. A. Buschauer für die interessante Themenstellung, seine wissenschaftlichen Anregungen und Förderung sowie für seine konstruktive Kritik bei der Durchsicht dieser Arbeit, Herrn Prof. Dr. G. Bernhardt für seine entgegengebrachte Hilfsbereitschaft bei analytischen Problemen, Herrn Prof. Dr. S. Elz und seinen Mitarbeitern für die Durchführung der organpharmakologischen Untersuchungen am Meerschweinchen und für die Erstellung des Zweitgutachtens, Herrn Prof. Dr. R. Seifert und seinen Mitarbeitern für die Möglichkeit zur Durchführung der GTPase Assays und die Testung von Substanzen, Frau K. Fisch für die zuverlässige und schnellstmögliche Durchführung der GTPase Assays, Frau E. Schreiber für die Durchführung der Ca2+ Assays, Frau S. Bollwein für die Durchführung der CE - Experimente, Herrn D. Schnell und seiner Praktikantin Stefanie Reeh für die Testung der Substanzen an rekombinanten H3 und H4 Membranen, Herrn M. Keller für die Hilfe bei Problemen an der HPLC-Anlage, allen Mitarbeitern der analytischen Abteilungen der Fakultät für die Aufnahme der NMR- und Massenspektren, sowie der Durchführung der Elementaranalysen, der „Histamin-Gruppe“ (Herrn T. Birnkammer, Frau D. Erdmann, Herrn Dr. P. Ghorai, Herrn P. Igel, Herrn J. Mosandl, Herrn Dr. H. Preuß und Herrn D. Schnell) für die gute, interdisziplinäre Zusammenarbeit, Herrn T. Birnkammer, Frau D. Erdmann, Herrn Dr. P. Ghorai und Frau G. Petrache für eine schöne und entspannte Atmosphäre im gemeinsamen Labor, Herrn M. Lopuch für die Synthese von H2-Agonisten im Rahmen seiner Masterarbeit und die Bereitstellung dieser Daten, meinen studentischen Hilfskräften und Schwerpunktpraktikanten für ihre engagierte Mitarbeit im Labor, Frau S. Heinrich, Herrn P. Richthammer und Frau M. Wechler für die Hilfsbereitschaft und Unterstützung bei vielen organisatorischen und technischen Dingen, allen Mitgliedern des Lehrstuhls für ihre Kollegialität, Hilfsbereitschaft und ein gutes Arbeitsklima, dem Gaduiertenkolleg 760 der DFG für die finanzielle Unterstützung und wissenschaftliche Förderung, all meinen Freunden für ihren Beistand und den Spaß, auch außerhalb der Uni, vor allem Frau S. Schmidt für eine einmalige, neunjährige WG-Zeit und Frau K. Wiesler für die Unterstützung, den Zusammenhalt und die unzähligen Mittags- und Kaffeepausen während der letzten neun Jahre, meiner Familie, ganz besonders meinen Eltern für ihre Geduld, Unterstützung und Hilfe in jeglicher Art und Weise in all den Jahren, und vor allem meinem Freund Martin. Contents Contents Chapter 1................................................................................................................... 1 Introduction............................................................................................................... 1 1.1. Histamine receptors ..................................................................................... 1 1.2. Histamine H2 receptor .................................................................................. 4 1.2.1. Distribution and function........................................................................ 4 1.2.2. Signal transduction mechanisms............................................................... 6 1.2.3. Histamine H2 receptor agonists ................................................................. 6 1.2.3.1. Small molecule histamine H2 receptor agonists...................................... 6 1.2.3.2. Imidazolylpropylguanidines .................................................................... 7 1.3. G protein coupled receptors and oligomerization ....................................... 11 1.3.1. Classification and activation of G protein coupled receptors............... 11 1.3.2. GPCR oligomerization......................................................................... 12 1.4. References..................................................................................................... 15 Chapter 2................................................................................................................. 26 Scope of the Thesis................................................................................................ 26 2.1. References..................................................................................................... 28 Chapter 3................................................................................................................. 29 G N -Acylated Imidazolylpropylguanidines – Synthesis and Histamine H2 Receptor Agonistic Activity................................................................................... 29 3.1. Introduction ................................................................................................ 29 3.2. Chemistry ................................................................................................... 31 3.3. Pharmacological results and discussion..................................................... 38 3.3.1. Histamine H2 receptor agonism........................................................... 39 3.3.1.1. H2R agonism on the isolated guinea pig right atrium ........................ 39 3.3.1.2. Agonist potencies and efficacies at hH2R-GsαS and gpH2R-GsαS fusion proteins .......................................................................................................... 42 3.3.2. Receptor selectivity ................................................................................. 48 3.3.2.1. Activity on the human histamine H1 receptor on U-373 MG human cells................................................................................................................ 48 3.3.2.2. Agonist potencies and efficacies at the hH3R and hH4R ................... 49 Contents 3.4. Summary........................................................................................................ 50 3.5. Experimental section...................................................................................... 52 3.5.1. General conditions................................................................................... 52 3.5.2. Preparation of ketones ............................................................................ 53 3.5.3. Preparation of ethyl (E,Z)-alkenoates ...................................................... 57 3.5.4. Preparation of ethyl alkanoates ............................................................... 61 3.5.5. Preparation of phenylalkanoic acids ........................................................ 66 3.5.6. Preparation of cyclohexylalkanoic acids .................................................. 74 3.5.7. Preparation of the imidazolylpropylguanidine building blocks.................. 78 3.5.8. Preparation of trityl-protected imidazolylpropylguanidines....................... 82 3.5.9. Preparation of acylguanidines ................................................................. 93 3.4. References................................................................................................111 Chapter 4................................................................................................................118 NG-Acylated Aminothiazolylpropylguanidines: Towards Selective Histamine H2R Agonists..........................................................................................................118 4.1. Introduction ...............................................................................................118 4.2. Chemistry ..................................................................................................119 4.3. Pharmacological results and discussion....................................................123 4.3.1. Histamine H2 receptor agonism..........................................................123 4.3.1.1. Agonist potencies and efficacies at the guinea pig right atrium........123 4.3.1.2. Agonist potencies and efficacies at hH2R-GsαS and gpH2R-GsαS in the GTPase assay ..............................................................................................126 4.3.2. Receptor selectivity ............................................................................132 2+ 4.3.2.1. Histamine H1 receptor antagonism on U-373 MG cells (Ca -assay) ......................................................................................................................132 4.3.2.2. Activities on the human H3 and H4 receptors (GTPase assay) ........132 4.4. Summary...................................................................................................133 4.5. Experimental section .................................................................................135
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