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Neue Wirkstoffkandidaten Mit Histamin-H3- Rezeptor-Pharmakophor Auf Dem Gebiet

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Neue Wirkstoffkandidaten Mit Histamin-H3- Rezeptor-Pharmakophor Auf Dem Gebiet Neue Wirkstoffkandidaten mit Histamin-H3- Rezeptor-Pharmakophor auf dem Gebiet neurodegenerativer Erkrankungen Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Markus Martin Falkenstein aus Bochum Düsseldorf, März 2021 aus dem Institut für Pharmazeutische und Medizinische Chemie der Heinrich-Heine-Universität Düsseldorf Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Berichterstatter: 1. Univ.-Prof. Dr. Dr. hc. Holger Stark 2. Univ.-Prof. Dr. Thomas Kurz Tag der mündlichen Prüfung: 26.05.2021 Danksagung Ich bin stolz und glücklich, mich bei meinem Doktorvater Herrn Prof. Dr. Dr. Holger Stark bedanken zu können. Ich bedanke mich für die Möglichkeit der Promotion in seinem Arbeitskreis am Institut für Medizinische und Pharmazeutische Chemie der Heinrich-Heine- Universität Düsseldorf und für das äußerst interessante Thema, das ich während meiner Promotion bearbeiten konnte. Ich bedanke mich für einen regen wissenschaftlichen Austausch, fachliche Expertise, konstruktive Diskussionen und Hilfestellung. Des Weiteren bedanke ich mich für hilfreiche Gespräche auch abseits von Wissenschaft und Forschung. Ich bedanke mich bei Herrn Prof. Dr. Thomas Kurz, der mit als Co-Betreuer und Zweitkorrektor jederzeit für einen konstruktiven Austausch zur Verfügung stand. Ich bedanke mich bei meinem Arbeitskreis, der mir in wechselnder Zusammensetzung sowohl fachlich als auch privat einen großen Rückhalt geboten hat. Im Besonderen bedanke ich mich bei Frau Annika Frank, Frau Kathrin Grau und Herrn David Reiner-Link für die pharmakologische Charakterisierung meiner Substanzen. In diesem Zusammenhang danke ich auch Prof. Wieslawa Agnieszka Fogel und ihrem Arbeitskreis im Dept. of Hormone Biochemistry, Medical University of Łodz, Polen für die Bestimmung der ZNS-Gängigkeit in In-vivo-Experimenten. Ich bedanke mich bei Dr. Bassam Sadek und seinem Arbeitskreis im Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, UAE für die Testung meiner Substanzen in In-vivo- Experimenten und bei Prof. Dr. Dieter Willbold und seinem Arbeitskreis im Forschungszentrum Jülich für die Bestimmung der Aβ1-42- Affinität mittels SPR-Spektroskopie. Ich bedanke mich bei meinen Kollegen Hjördis, Mariam, Luisa, Stefanie, Jens, Kiril, Stephen, Lars Stank, Markus, Lars Seifert, Patrick und Cristian Di Biase, der ein Stück Italien ins Labor gebracht hat, für eine spannende Zeit im Arbeitskreis. In besonderer Weise möchte ich mich bei Aleks und Mili bedanken, die mir durch den Laboralltag und „Exkursionen“ zu echten Freunden geworden sind. Ich bedanke mich bei meiner Familie für die bedingungslose Unterstützung und den Zuspruch während meines Studiums und der gesamten Promotionszeit. Ich habe durch Euch die Freiheit gehabt, meine Ziele zu verfolgen und zu erreichen. Mein größter Dank geht an meine Frau Laura. Ohne Dich wäre das Studium und die Promotion weder vorstellbar noch bedeutsam gewesen. Für Laura Inhaltsverzeichnis Inhaltsverzeichnis ........................................................................................................................ I Kurzfassung ................................................................................................................................ 1 1 Einleitung ........................................................................................................................... 3 1.1 Neurodegenerative Erkrankungen ............................................................................... 3 1.1.1 Gemeinsamkeiten neurodegenerativer Erkrankungen.......................................... 3 1.1.2 Morbus Alzheimer ................................................................................................ 6 1.1.3 Schizophrenie ..................................................................................................... 16 1.2 Histamin ..................................................................................................................... 21 1.2.1 Physiologie des Histamins ................................................................................. 21 1.2.2 G-Protein gekoppelte Rezeptoren ...................................................................... 23 1.2.3 Histaminrezeptor-Subtypen ................................................................................ 27 1.2.4 Der Histamin-H3-Rezeptor als pharmakologische Zielstruktur ......................... 35 1.3 Dopamin .................................................................................................................... 38 1.3.1 Biosynthese und Metabolismus .......................................................................... 38 1.3.2 Dopaminerge Leitungsbahnen im ZNS .............................................................. 39 1.3.3 Dopaminrezeptoren ............................................................................................ 40 1.3.4 D2R und D3R als pharmakologische Zielstrukturen ........................................... 42 2 Zielsetzung ....................................................................................................................... 46 3 Synthese ........................................................................................................................... 50 3.1 Rationale Arzneistoffentwicklung ............................................................................. 50 3.2 Synthese von Vorstufen mit H3R-Pharmakophor ...................................................... 56 3.3 Synthese von 2,5-Diketopiperazinen ......................................................................... 58 3.3.1 Synthese von Aminosäurevorstufen ................................................................... 58 3.3.2 Synthese von 2,5-Diketopiperazinen .................................................................. 59 3.3.3 Stereochemische Betrachtung der 2,5-Diketopiperazinsynthese ....................... 62 3.4 Synthese von α,β-ungesättigten 2,5-Diketopireazinen .............................................. 65 3.5 Synthese von 2-Ketopiperazinen ............................................................................... 70 I 3.5.1 Synthese von (S)-Hexahydropyrrolo[1,2-a]pyrazinon-Derivaten ...................... 70 3.5.2 Synthese von Piperazin-2-on-Derivaten ............................................................. 74 3.6 Synthese von C-substituierten Piperazinen ............................................................... 75 3.7 Synthese von N-substituierten Piperazinen ............................................................... 77 3.7.1 Synthese von Piperazin N-Benzyl- und Benzoylderivaten ................................ 77 3.7.2 Synthese von N-L-Prolin-yl-Piperazinderivaten ................................................. 78 3.7.3 Synthese von Zimtsäureamiden ......................................................................... 80 3.7.4 Übersicht der Histamin-H3R-Liganden .............................................................. 82 3.8 Synthese von Piperazinderivaten mit Dopamin-D2R/ D3R-Pharmakophor .............. 83 3.8.1 Synthese von MTDL mit D2R/ D3R-Antagonisten-Pharmakophor ................... 83 3.8.2 Synthese von MTDL mit D2R/ D3R-Agonisten-Pharmakophor ........................ 86 3.9 Zusammenfassung Synthese ...................................................................................... 88 4 Pharmakologische Testung .............................................................................................. 90 4.1 Histamin-H3-Rezeptor ............................................................................................... 90 4.1.1 H3R-Affinität von 2,5-Diketopiperazinen .......................................................... 91 4.1.2 H3R-Affinität von α,β-ungesättigten 2,5-Diketopiperazinen ............................. 92 4.1.3 H3R-Affinität von 2-Ketopiperazinen ................................................................ 93 4.1.4 H3R-Affinität von C-substituierten Piperazinen ................................................ 95 4.1.5 H3R-Affinität von N-substituierten Piperazinen ................................................ 96 4.1.6 H3R-Affinität von Zimtsäureamiden und Analoga ............................................ 98 4.2 Amyloid-Beta-Interaktion ....................................................................................... 100 4.3 In-vivo-Testung von Verbindung 52e ..................................................................... 104 4.4 Testung der IGF1-Freisetzung ................................................................................. 104 4.5 Dopamin-D2/ D3-Rezeptor ....................................................................................... 105 4.5.1 D2R- und D3R-Affinität von Methoxyphenyl-piperazinen .............................. 105 4.5.2 D2R- und D3R-Affinität von para-Alkoxy-phenoxy-ethyl-piperazinen .......... 107 4.5.3 In-vivo-Testung von Verbindung 101 .............................................................. 108 5 Diskussion ...................................................................................................................... 112 II 5.1 MTDL für die Therapie von Morbus Alzheimer ..................................................... 112 5.2 MTDL für die Therapie der Schizophrenie ............................................................. 120 6 Zusammenfassung .........................................................................................................
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