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Novel Nicotinic Acetylcholine Receptor Ligands Based Novel Nicotinic Acetylcholine Receptor Ligands based on Cytisine and Choline: Synthesis, In vitro Evaluation and Structure-Activity Relationships Dissertation zur Erlangung des Doktorgrades (Dr.rer.nat.) der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von Lenka Munoz aus Nové Zámky (Slowakei) Bonn 2005 Angefertigt mit Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn 1. Referent: PD Dr. Daniela Gündisch 2. Referent: Prof. Dr. Christa E. Müller Tag der Promotion: 2. November 2005 Die vorliegende Arbeit wurde im Zeitraum von Oktober 2001 bis September 2005 in der Abteilung Pharmazeutische Chemie des Pharmazeutischen Institutes der Rheinischen Friedrich-Wilhelm-Universität Bonn unter der Leitung von PD Dr. Daniela Gündisch angefertigt. Ich danke herzlich Frau PD Dr. Daniela Gündisch für die wissenschaftliche Leitung dieser Arbeit sowie für ihre hervorragende Betreuung. Mein Dank gilt ebenfalls Frau Prof. Dr. Christa E. Müller für die freundliche Übernahme des Koreferates. For Alex … Table of Contents 1 Introduction ...................................................................................................................... 1 1.1 Nicotinic Acetylcholine Receptors............................................................................ 1 1.1.1 The Structure of nAChRs ................................................................................. 1 1.1.2 nAChRs in Human Pathology .......................................................................... 4 1.2 Nicotinic Acetylcholine Receptors Ligands .............................................................. 6 1.2.1 Class A: Acyclic HBA/ π and Acyclic Cation...................................................... 7 1.2.2 Class B: Cyclic HBA/ π and Acyclic Cation ....................................................... 8 1.2.3 Class C: Cyclic HBA/ π and Cyclic Cation......................................................... 9 1.2.4 Class D: Acyclic HBA/ π and Cyclic Cation ..................................................... 13 1.2.5 Class E: HBA/ π and Cation in Fused Ring System........................................ 15 1.3 nAChR Pharmacophore Models ............................................................................ 17 2 Objectives ...................................................................................................................... 21 3 Project I: Development of Novel nAChR Ligands based on Cytisine............................. 25 3.1 Cytisine as a Lead Compound............................................................................... 25 3.1.1 Introduction .................................................................................................... 25 3.1.2 Pharmacological Characterisation of Cytisine................................................ 26 3.1.3 Radioligand [ 3H]Cytisine................................................................................. 28 3.1.4 Cytisine in Human Medicine........................................................................... 29 3.1.5 Total Synthesis of Cytisine............................................................................. 30 3.1.6 Modification of the Cytisine Scaffold .............................................................. 32 3.1.7 Structure-Activity Relationship of Cytisine Derivatives................................... 35 3.2 Syntheses of Novel nAChRs based on Cytisine .................................................... 41 3.2.1 Suzuki Cross-Coupling Reaction ................................................................... 41 3.2.1.1 Mechanism................................................................................................. 42 3.2.1.2 Reaction Conditions ................................................................................... 44 3.2.1.2.1 Palladium Catalyst ............................................................................... 44 3.2.1.2.2 Base..................................................................................................... 44 3.2.1.2.3 Organoboron Coupling Partner ............................................................ 45 3.2.1.2.4 Organic Halides / Pseudohalides as Coupling Partners ...................... 48 3.2.2 Suzuki vs. Stille Cross-Coupling Reaction ..................................................... 49 3.2.3 Suzuki Reaction in Microwave Assisted Organic Synthesis .......................... 50 3.2.3.1 Microwave .................................................................................................. 51 3.2.3.2 Microwaves as a Heating Source in Organic Synthesis............................. 51 3.2.3.3 Microwaves in Suzuki Cross-Coupling Reaction........................................ 54 3.2.4 Isolation of Cytisine ........................................................................................ 56 3.2.4.1 Introduction................................................................................................. 56 3.2.4.2 Method / Results......................................................................................... 56 3.2.4.3 Discussion .................................................................................................. 57 3.2.5 Protection of the Secondary Amino Group of Cytisine ................................... 57 3.2.5.1 Introduction................................................................................................. 57 3.2.5.2 Method / Results......................................................................................... 58 3.2.5.3 Discussion .................................................................................................. 59 3.2.6 2-Pyridone Scaffold ........................................................................................ 59 3.2.7 Bromination of Cytisine .................................................................................. 61 3.2.7.1 Introduction................................................................................................. 61 3.2.7.2 Method / Results......................................................................................... 62 3.2.7.3 Discussion .................................................................................................. 63 3.2.8 3-Phenyl Analogues of Cytisine ..................................................................... 64 3.2.8.1 Introduction................................................................................................. 64 3.2.8.2 Method / Results......................................................................................... 66 3.2.8.3 Discussion .................................................................................................. 67 3.2.9 5-Phenyl Analogues of Cytisine ..................................................................... 68 3.2.9.1 Introduction................................................................................................. 68 3.2.9.2 Method / Results......................................................................................... 69 3.2.9.3 Discussion .................................................................................................. 70 3.2.10 Heterocyclic Derivatives of Cytisine ............................................................... 72 3.2.10.1 Introduction............................................................................................. 72 3.2.10.2 Method / Results..................................................................................... 73 3.2.10.3 Discussion .............................................................................................. 76 3.2.11 3,5-Disubstituted Analogues of Cytisine......................................................... 77 3.2.11.1 Introduction............................................................................................. 77 3.2.11.2 Method / Results..................................................................................... 78 3.2.11.3 Discussion .............................................................................................. 78 3.2.12 Removal of the tBOC Protecting Group ......................................................... 79 3.2.12.1 Introduction............................................................................................. 79 3.2.12.2 Method/Results....................................................................................... 80 3.2.12.3 Discussion .............................................................................................. 80 3.3 1H and 13 C NMR Chemical Shifts Assignment for the Novel nAChRs Ligands ...... 82 3.3.1 Overview of used NMR Spectroscopy Methods............................................. 82 3.3.2 Project ............................................................................................................ 83 3.3.3 Spectral Assignments of 1H and 13 C Chemical Shifts..................................... 85 3.3.3.1 Cytisine 27 .................................................................................................. 85 3.3.3.2 3-Phenyl- and 5-Phenyl-cytisine 93e & 103e ............................................. 95 3.3.3.3 3-Aryl Analogues of Cytisine .................................................................... 104 3.3.3.4 5-Aryl Analogues of Cytisine .................................................................... 109 3.3.3.5 Heterocyclic Analogues of Cytisine.........................................................
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