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I N a U G U R a L D I S S E R T a T I O N Synthese und Charakterisierung von Liganden spannungsabhängiger KV7-Kaliumkanäle auf Grundlage der Arzneistoffe Flupirtin und Retigabin I n a u g u r a l d i s s e r t a t i o n zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) der Mathematisch-Naturwissenschaftlichen Fakultät der Universität Greifswald vorgelegt von Christian Bock Greifswald, Mai 2019 Dekan: Prof. Dr. Werner Weitschies 1. Gutachter: Prof. Dr. Andreas Link 2. Gutachter: Prof. Dr. Holger Stark Tag der Promotion: 19.07.2019 Inhaltsverzeichnis Abkürzungsverzeichnis .................................................................................................. IV 1 Einleitung und Zielstellung ....................................................................................... 1 1.1 Physiologie spannungsabhängiger KV7-Kaliumkanäle ...................................... 1 1.2 Modulation von KV7-Kanälen............................................................................. 2 1.3 Das Analgetikum Flupirtin ................................................................................. 3 1.4 Das Antikonvulsivum Retigabin ......................................................................... 4 1.5 Bindetasche von Retigabin und Flupirtin ........................................................... 4 1.6 Bisher publizierte KV7-Kanal-Öffner .................................................................. 5 1.7 Therapeutisches Potential von KV7-Kanalöffnern .............................................. 7 1.8 Zielstellung der vorliegenden Arbeit .................................................................. 7 2 Methoden und Ergebnisse ....................................................................................... 8 2.1 Synthese der Flupirtin-Analoga ......................................................................... 8 2.2 Synthese der Retigabin-Analoga ......................................................................13 2.3 Synthese des Pyrimidin-Sulfids ........................................................................15 2.4 Bestimmung des Oxidationspotentials .............................................................16 2.5 Bestimmung der Lipophilie ...............................................................................17 2.6 Bestimmung der KV7.2/3-Modulation ................................................................17 2.7 Bestimmung der Hepatotoxizität ......................................................................17 3 Diskussion und Ausblick .........................................................................................19 4 Literaturverzeichnis .................................................................................................22 5 Publikationen ..........................................................................................................29 Synthesis and potassium KV7 channel opening activity of thioether analogues of the analgesic flupirtine ......................................................................................................29 Flupirtine Analogues: Explorative Synthesis and Influence of Chemical Structure on KV7.2/KV7.3 Channel Opening Activity ........................................................................35 How to replace the lost keys? Strategies towards safer KV7 channel openers ............40 Sulfide Analogues of Flupirtine and Retigabine with Nanomolar KV7.2/KV7.3 Channel Opening Activity .........................................................................................................60 Flupirtine and Retigabine as Templates for Ligand-based Drug Design of KCNQ2/3 activators ....................................................................................................................75 Simultaneous quantification of acidic and basic flupirtine metabolites by supercritical fluid chromatography according to European Medicines Agency validation ................87 Thioether als Modulatoren von KV7.2/KV7.3-Kanälen ................................................ 101 6 Veröffentlichungsverzeichnis................................................................................. 152 6.1 Wissenschaftliche Artikel ............................................................................... 152 6.2 Patentschrift ................................................................................................... 152 6.3 Posterpräsentationen ..................................................................................... 152 Abkürzungsverzeichnis Abkürzungsverzeichnis ACN Acetonitril ALAT Alanin-Aminotransferase ALS amyotrophe Lateralsklerose ASAT Aspartat-Aminotransferase BfArM Bundesinstitut für Arzneimittel und Medizinprodukte BFNE benigne familiäre Neugeborenenepilepsie DCM Dichlormethan DMA N,N-Dimethylanilin DMAP 4-(Dimethylamino)pyridin DMF N,N-Dimethylformamid DMSO Dimethylsulfoxid EC50 Konzentration, bei der ein halbmaximaler Effekt auftritt EPA United States Environmental Protection Agency FILI flupirtine induced liver injury FLIPR fluorescent imaging plate reader GABA -Aminobuttersäure HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorphosphat HEK human embryonic kidney cells IKs repolarisierender Kaliumstrom + IM M-type K current IMS imaging mass spectrometry LD25 Konzentration, welche die Zellviabilität auf 75 % senkt mAChR muskarinischer Acetylcholinrezeptor mCPBA meta-Chlorperoxybenzoesäure NBS N-Bromsuccinimid NSAR nichtsteroidales Antirheumatikum PIP2 Phosphatidylinositol-4,5-bisphosphonat PLC Phospholipase C PRAC Pharmacovigilance Risk Assessment Center SAR structure activity relationship Ssm Scolopendra subspinipes mutilans IV Abkürzungsverzeichnis TAMH transforming growth factor-a transgenic mouse hepatocyte TFA Trifluoressigsäure THF Tetrahydrofuran TsCl para-Toluensulfonsäurechlorid VSD voltage-sensing domain (Spannungssensor-Domäne) ZNS zentrales Nervensystem V Einleitung und Zielstellung 1 Einleitung und Zielstellung 1.1 Physiologie spannungsabhängiger KV7-Kaliumkanäle Bereits im Jahr 1980 konnte durch Brown und Adams ein spannungsabhängiger Kaliumstrom in sympathischen Neuronen des nordamerikanischen Ochsenfrosches (Rana catesbeiana) nachgewiesen werden[1]. Dabei wurde mittels Voltage-Clamp-Experimenten gezeigt, dass die Stärke des Kaliumstroms vom Membranpotential abhängig ist. Während bei Potentialen unter −60 mV kein Kaliumstrom zu beobachten war, steigerte sich dieser mit zunehmendem Potential in sigmoider Form und erreichte ein Plateau bei ca. −10 mV. Die zu beobachtende Hemmung des Kaliumstroms durch Aktivierung muskarinerger Rezeptoren führte zur Benennung desselben als M-current (IM). Die dem Ionenstrom zugrunde liegenden Kanäle konnten erst ca. 20 Jahre später identifiziert werden. Zunächst wurde 1996 durch Wang et al. das Gen für das KVLQT1-Protein (später als KV7.1 bekannt) beschrieben, welches aufgrund seiner Ähnlichkeit zu schon bekannten spannungsabhängigen Kaliumkanälen als eben solcher Kanal identifiziert wurde[2]. Die überwiegende Expression des Proteins in Herz und in der Niere, aber die Abwesenheit im Gehirn zeigte, dass es sich nicht um die molekulare Grundlage des IM handeln konnte. Im selben Jahr wurde auch der nKQT2-Kanal (später als KV7.2 bezeichnet) durch die Entschlüsselung des Genoms eines Fadenwurms (Caenorhabiditis elegans) entdeckt[3]. Der dritte Vertreter der Proteinfamilie konnte [4] 1998 als KCNQ3 (später als KV7.3 bezeichnet) identifiziert werden . Wenige Monate danach wurde dann ein [5] heteromerer Kanal aus KV7.2- und KV7.3-Untereinheiten als Grundlage des IM publiziert . Komplettiert wurde die KV7-Familie durch die Entdeckungen von KCNQ4 (KV7.4) im Jahre 1999 sowie KCNQ5 (KV7.5) im Jahre 2000[6,7]. [6,8] Die Proteine der KV7-Familie sind aus 676–932 Aminosäuren aufgebaut . Diese teilen sich auf in sechs transmembranäre Domänen (S1–S6), sowie eine Schlaufe zwischen S5–S6 und lange intrazelluläre C- und N- Termini (siehe Abbildung 1). Der Abschnitt S1–S4 fungiert als Spannungssensor-Domäne (voltage-sensing domain, VSD), während von dem Abschnitt S5–S6 die ionenselektive Pore gebildet wird. KV7-Kanäle werden aus vier Untereinheiten aufgebaut, wobei fast ausschließlich Tetramere aus Poren-formenden -Untereinheiten (KV7.1–5) funktionsfähige Kanäle bilden. Lediglich das KV7.1-Protein neigt dazu auch mit Poren-losen - Untereinheiten (vor allem KCNE1 und KCNE3) Kanäle zu bilden[8,9]. Neben den möglichen Homotetrameren, welche aus vier gleichen -Untereinheiten bestehen, werden auch häufig Heterotetramere aus zwei verschiedenen -Untereinheiten beschrieben. Diese setzten sich in symmetrischer Weise zusammen (siehe Abbildung 1). Die Affinität der Untereinheiten zueinander ist verschieden stark ausgeprägt. So bildet das KV7.1- Protein bevorzugt homomere Kanäle oder assembliert, wie bereits erwähnt, mit -Untereinheiten. Heterotetramere mit anderen -Untereinheiten sind für KV7.1 nicht beschrieben. Die KV7.2-Untereinheit kann Homotetramere ausbilden, diese zeigen allerdings einen elffach niedrigeren Kaliumstrom als das Heterotetramer mit KV7.3, entsprechend sollte die physiologische Bedeutung dieser Homotetramere von [5] vernachlässigbarer Bedeutung sein . Für KV7.3 gilt Gleiches, so zeigt das Homotetramer einen deutlich geringeren Kaliumstrom als das Heterotetramer mit KV7.2. KV7.3 bildet allerdings zusätzlich Kanäle mit KV7.4 bzw. KV7.5. Auch für das KV7.4-Protein sind Homotetramere beschrieben und neben der bereits erwähnten [8] Konjugation mit KV7.3 werden auch Heterotetramere mit KV7.5 berichtet . KV7-Kanäle
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