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Pentaerithrityltetranitrat, Glyceryltrinitrat, Deren Bioaktive Metabolite Und Andere NO-Basierende Vasodilatoren ― Beziehungen Zwischen Struktur Und Wirkung

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Pentaerithrityltetranitrat, Glyceryltrinitrat, Deren Bioaktive Metabolite Und Andere NO-Basierende Vasodilatoren ― Beziehungen Zwischen Struktur Und Wirkung Pentaerithrityltetranitrat, Glyceryltrinitrat, deren bioaktive Metabolite und andere NO-basierende Vasodilatoren ― Beziehungen zwischen Struktur und Wirkung Dissertation zur Erlangung des akademischen Grades doctor rerum naturalium (Dr. rer. nat.) vorgelegt dem Rat der Biologisch-Pharmazeutischen Fakultät der Friedrich-Schiller-Universität Jena von Andreas König geboren am 24. Februar 1977 in Mühlhausen/Thür. Gutachter: 1. Prof. Dr. Jochen Lehmann 2. Prof. Dr. Erika Glusa 3. Prof. Dr. Hans-Jürgen Duchstein Tag der öffentlichen Verteidigung: 29.02.2008 Danksagung Die vorliegende Arbeit wurde im Zeitraum zwischen Januar 2004 bis Dezember 2007 am Institut für Pharmazie der Friedrich-Schiller Universität Jena durchgeführt. In besonderer Weise möchte ich zwei Menschen gleichermaßen sehr herzlich danken. Zum einen Frau Professor Dr. Erika Glusa, die mich mit viel Sachverstand, Tatendrang und akademischer Disziplin, gleichzeitig verbunden mit menschlicher Herzlichkeit, an die pharmakologischen Fragestellungen herangeführt hat und in allen Phasen der Arbeit mir äußerst hilfreich zur Seite stand. Ebenso gilt mein Dank Herrn Professor. Dr. Jochen Lehmann, der das Thema anregte, die Arbeit mit großem Einsatz unterstützte und mit seiner freundlichen, entgegenkommenden und kreativen Art eine angenehme Arbeitsatmosphäre ermöglichte. Außerdem möchte ich ihm dafür danken, daß ich die in Erfurt begonnenen Arbeiten in Jena in seiner Arbeitsgruppe fortsetzen konnte und mir viele schöne und unvergessliche Momente wie die NO-Konferenz in Monterey oder die PETN-Expertentreffen ermöglicht wurden. Herrn Professor Dr. Hans-Jürgen Duchstein danke ich für die freundliche Übernahme des Korreferats. Für die große Kooperationsbereitschaft, erfolgreiche Zusammenarbeit und Unterstützung in den gemeinsamen Projekten danke ich Herrn PD Dr. habil. Michael Decker, Herrn Dr. Dirk Stalleicken, Herrn Dr. Dr. habil. Andreas Daiber, Herrn Dr. Jörg Konter, Frau Kathrin Lange sowie Frau Carolin Roegler. Bedanken möchte ich mich nicht zuletzt von ganzem Herzen bei allen Kollegen und den vielen gewonnenen Freunden im Institut, mit denen ich neben der angenehmen Zusammenarbeit und Hilfsbeitschaft eine wunderbare gemeinsame Zeit in Jena verleben durfte. Mein privater und größter Dank gebührt meiner Familie, meinen Eltern Doris und Gerhard König sowie meinem Bruder Alexander König, die mich in jederlei Hinsicht auf meinem bisherigen Lebensweg unterstützt und gefördert hat, tiefsten Dank auch an Kathi Gülland einfach für eine schöne gemeinsame Zeit. Inhaltsverzeichnis I 1. Einleitung 1 1.1. Pharmakotherapie kardiovaskulärer Erkrankungen 1 1.1.1. Die koronare Herzkrankheit 1 1.1.2. Stellenwert und Anwendungsgebiete organischer Nitrate 2 Das erste organische Nitrat: Glyceryltrinitrat 2 Entwicklung langwirksamer Nitrate 4 Aktueller Arzneimittelbestand an Koronarmitteln 7 Vergleichende Bewertung 9 1.2. Wirkmechanismus organischer Nitrate 10 1.2.1. Antiischämisches Prinzip 10 1.2.2. Wirkprinzip auf molekularer Ebene 11 1.2.3. Bioaktivierung organischer Nitrate 13 NO aus Nitraten? 13 Verschiedene Bioaktivierungshypothesen 14 Die mitochondriale Aldehyddehydrogenase 15 Hochpotenter Stoffwechselweg über ALDH-2 16 Niedrigpotenter Stoffwechselweg über ? 18 1.3. Nitrattoleranz 18 1.3.1. Pseudotoleranz 19 1.3.2. Klassische Toleranz 20 Erklärungsansätze und –theorien 20 2. Zielstellung 23 2.1. Vorbemerkungen 23 2.2. Aufgabenstellungen 25 3. Übersicht der Veröffentlichungen 29 II Inhaltsverzeichnis 4. Veröffentlichungen 33 Veröffentlichung 1 33 Pharmakologische Charakterisierung von Pentaerithrityltetranitrat, seinen nitrathaltigen Metaboliten und anderen organischen Nitraten an der isolierten Pulmonalarterie des Schweins. König, Andreas; Pietig, Imke; Homann, Alexander; Glusa, Erika; Fricke, Uwe; Lehmann, Jochen. In: ERDMANN, E.; MUTSCHLER, E.; STALLEICKEN, D. (Hrsg.): Pentaerithrityltetranitrat: Evidenzorientiertes Therapiekonzept kardialer Erkrankungen. Steinkopff Verlag, Darmstadt (2004), 59-68. Veröffentlichung 2 43 Synthesis and vasorelaxant properties of hybrid molecules out of NO-donors and the beta-receptor blocking drug propranolol. Decker, Michael; König, Andreas; Glusa, Erika; Lehmann, Jochen. Bioorganic & Medicinal Chemistry Letters (2004), 14, 4995-7. Veröffentlichung 3 46 Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate. König, Andreas; Lange, Kathrin; Konter, Jörg; Daiber, Andreas; Stalleicken, Dirk; Glusa, Erika; Lehmann, Jochen. Journal of Cardiovascular Pharmacology (2007), 50, 68-74. Veröffentlichung 4 53 NO donors. Part 16: investigations on structure-activity relationships of organic mononitrates reveal 2-nitrooxyethylammoniumnitrate as a high potent vasodilator. König, Andreas; Roegler, Carolin; Lange, Kathrin; Daiber, Andreas; Glusa, Erika; Lehmann, Jochen. Bioorganic & Medicinal Chemistry Letters (2007), 17, 5881-5. Veröffentlichung 5 58 NO donors. Part 18: synthesis and vasorelaxant properties of the bioactive metabolites of GTN and PETN. Lange, Kathrin; König, Andreas; Roegler, Carolin; Seeling, Andreas; Lehmann, Jochen. Bioorganic & Medicinal Chemistry Letters. In Vorbereitung. Inhaltsverzeichnis III 5. Unveröffentlichte Ergebnisse 63 5.1. Einfluß der Nitratgruppenanzahl auf die vasodilatorische Potenz 63 5.2. Stärkere Vasoaktivität direkter NO-Donoren am Beispiel der NONOate im Vergleich zu organischen Nitraten 65 5.3. In vitro Wirkprofil von Nitraten, Nitriten und NONOaten 69 5.4. In vitro Kreuztoleranzentwicklung zwischen organischen Nitraten und Nitriten nach EC50-Bolusgabe 71 5.5. Vasodilatorische Eigenschaften von NSAID-Nitrat-Hybridmolekülen 73 5.6. Methoden zum Nachweis einer in vitro Nitrattoleranz 76 5.7. Untersuchungen zur Kreuztoleranzentwicklung GTN vs. 1,2-GDN 77 5.8. 2-Aminoethylnitrat: in vitro Toleranzuntersuchungen 79 5.9. 2-Aminoethylnitrat: Bioaktivierung über ALDH-2? 80 5.10. Untersuchung zur Bildung von ROS-Spezies bei einigen ausgewählten Mononitraten im Vergleich zu GTN 82 6. Diskussion 85 6.1. Einfluß der Nitratgruppenanzahl auf die Vasoaktivität 86 6.2. Einfluß des nitrattragenden Rests auf die Vasoaktivität 88 6.2.1. Synthese von strukturell verschiedenen organischen Mononitraten 88 6.2.2. Unterschiede in den Wirkaktivitäten und deren mögliche Ursache 91 6.3. Ein hochpotentes Mononitrat: 2-Aminoethylnitrat 92 6.4. Nitrat-Hybridverbindungen 94 6.5. Einfluß der Struktur organischer Nitrate auf die Toleranz 95 6.6. Erklärungsansätze für das klinische Wirkprofil von PETN 99 7. Zusammenfassung 101 IV Inhaltsverzeichnis 8. Conclusion 106 9. Literaturverzeichnis 10. Anhang Curriculum vitae Publikationsverzeichnis Selbstständigkeitserklärung Einleitung 1 1. Einleitung 1.1. Pharmakotherapie kardiovaskulärer Erkrankungen Kardiovaskuläre Erkrankungen sind gegenwärtig die häufigsten Todesursachen bei Frauen und Männern in Deutschland und im europäischen Ausland.1,2 Aus dem im Auftrag des Bundes vom Robert Koch-Institut jährlich erstellten Bericht „Gesundheit in Deutschland“ geht für 2006 hervor, dass im Bundesgebiet nahezu bei jedem zweiten Verstorbenen der Tod durch eine Erkrankung des Herz-Kreislaufsystems ausgelöst wurde. Dennoch sind die durch Herz-Kreislaufkrankheiten bedingten Todesfälle aufgrund stetig verbesserter Behandlungsmethoden seit 1990 in Deutschland kontinuierlich zurückgegangen.2 1.1.1. Die koronare Herzkrankheit Innerhalb der Gruppe der kardiovaskulären Erkrankungen kommt der koronaren oder auch ischämischen Herzkrankheit (KHK) die größte pathologische Bedeutung zu. Bei dieser chronischen Erkrankung der Koronargefäße wird durch morphologische oder pathophysiologische Veränderungen (z.B. Verengung oder Verschluss) eines oder mehrerer Gefäße eine Mangeldurchblutung der Herzens (Ischämie) verursacht. Damit ist in der Herzmuskulatur in Abhängigkeit von der Belastungssituation die Balance zwischen Sauerstoffangebot und -verbrauch gestört. Vor allem die größeren Koronargefäße können von der Manifestation einer Arteriosklerose betroffen sein, der sogenannten Koronarsklerose. Eine Einengung (Stenose) der koronaren Strombahn ist die Folge und kann zusätzlich durch Thrombenbildung zum teilweisen oder vollständigen Verschluss von Koronararterienästen führen. Die Koronarsklerose zählt zu den wichtigsten Ursachen der KHK. Neben dieser können aber auch Herzklappenfehler, vegetative Fehlsteuerungen, Arrhythmien, Anämien oder Bluthochdruck das Krankheitsbild herbeiführen oder begünstigen. Das hochvariable Spektrum der KHK erstreckt sich je nach Schweregrad von der asymptomatischen Form zu Beginn der Erkrankung über die Angina pectoris bis hin zum Myokardinfarkt (Herzinfarkt) oder Sekundenherztod („Herzschlag“). Als gesicherte Koronarsklerose-fördernde Risikofaktoren gelten Rauchen, Hypertonie, Hyperlipoproteinämie, Diabetes mellitus, Übergewicht und daraus schließlich resultierend 2 Einleitung die endotheliale Dysfunktion. Der Vermeidung dieser Risikofaktoren, auch durch präventivmedizinische und therapeutische Maßnahmen, kommt große Bedeutung zu .2,3 1.1.2. Stellenwert und Anwendungsgebiete organischer Nitrate Zum modernen Standard in der klinischen Behandlung der KHK zählen Bypassoperationen und insbesondere interventionelle Therapiestrategien wie die „Perkutane transluminale coronare Angioplastie“ (PTCA) sowie Stent-Implantationen.4,5 Diese Verfahren sollen im Sinne einer Revaskularisation der Koronargefäße die Durchblutung des Herzmuskels wiederherstellen. Ungeachtet dieser etablierten interventionellen Verfahren besteht
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