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1.2 Histamine Receptors

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1.2 Histamine Receptors Radioligand binding studies: Structure affinity relationships of antagonists at muscarinic, serotonergic and histaminergic receptor subtypes Radioligandbindungsstudien: Struktur-Wirkungs-Beziehungen von Antagonisten an muskarinischen, serotonergen und histaminergen Rezeptor Subtypen Dissertation for the Achievement of the Doctor’s Degree of Natural Sciences Submitted to the Faculty of Chemical and Pharmaceutical Sciences of the Johann Wolfgang Goethe-University Frankfurt am Main by Matthias Linder from Karlsruhe Frankfurt am Main, 2003 (DF 1) This work has been carried out from June 2001 until September 2003 at the Departments of Pharmacology and Pharmaceutical Biology (Faculty of Chemical and Pharmaceutical Sciences) of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany. Accepted as dissertation by the Faculty of Chemistry and Pharmaceutical Sciences of the Johann Wolfgang Goethe-University Frankfurt am Main Dean: Prof. Dr. H. Schwalbe 1st Referee: Prof. Dr. T. Dingermann 2nd Referee: Prof. Dr. G. Lambrecht Date of Disputatio: 12.03.2004 Danksagung Den Professoren Dr. T. Dingermann und Dr. G. Lambrecht danke ich als meinen Doktorvätern für die Überlassung des Themas und die Unterstützung bei der Anfertigung dieser Arbeit. Für das mir entgegengebrachte Vertrauen in Form einer sehr selbstverantwortlichen Arbeitsweise war ich sehr dankbar. Insbesondere Professor Dr. Lambrecht danke ich für die ständige Bereitschaft sich spontan die Zeit zu Gesprächen über Probleme meiner Arbeit zu nehmen und sein oft geradezu unheimliches Literaturgedächtnis uns Doktoranden zum Vorteil werden zu lassen. Mein Dank gilt Herrn Martin Walter aus dem Institut für Pharmazeutische Chemie von Prof. Dr. C. Noe, Wien, für die Synthese der Glycopyrroniumderivate, dem Arbeitskreis von Prof. Dr. S. Elz, Institut für Pharmazeutische Chemie, Regensburg, für das Überlassen der Ondansetron- und Metoclopramid-Analoga, PD Dr. M. Brüss, Institut für Pharmakologie und Toxikologie, Bonn, für die Bereitstellung der 5-HT3 und 5-HT4 Membranen, Prof. Dr. R. Leurs und Prof. Dr. H. Timmerman, Amsterdam, für das Überlassen der H1-Zelllinie, Dr. U. Moser und U. Hermanni aus unserem Institut, für die Synthese der McN-Derivate und besonders Frau Angela Bauer aus dem Arbeitskreis von Prof. Dr. G. Dannhardt, Institut für Pharmazeutische Chemie, Mainz, für den Kampf mit der Synthese der Dimethinden-Analoga. Den Damen im Sekretariat danke ich für die immer freundliche Hilfe bei der Lösung meiner administrativen Probleme und für die korrekte Umsetzung der neuen Ausgabeverordnung für Büromaterial. Ich möchte mich an dieser Stelle bei meinen Kollegen am Pharmakologischen Institut, allen voran bei meinen Mitdoktoranden, bedanken, die diese Zeit für mich zu einer schönen Erinnerung werden lassen, die durch Kollegialität und gute Zusammenarbeit geprägt war. Ich hoffe, dass die hier neu entstandenen Freundschaften noch lange Zeit Bestand haben werden. Besonderen Dank schulde ich meiner Frau und meinen Eltern für Ihre fortwährende moralische und finanzielle Unterstützung meiner Tätigkeiten. Table of Contents TABLE OF CONTENTS 1 INTRODUCTION ..................................................................................................... 1 1.1 Muscarinic receptors .......................................................................................... 2 1.1.1 Signal transduction ................................................................................ 3 1.1.2 Receptor desensitization and sequestration .......................................... 5 1.1.3 Receptor distribution in the periphery .................................................... 5 1.1.3.1 M1 receptors ................................................................................ 5 1.1.3.2 M2 receptors ................................................................................ 6 1.1.3.3 M3 receptors ................................................................................ 6 1.1.3.4 M4 receptors ................................................................................ 7 1.1.3.5 M5 receptors ................................................................................ 7 1.1.4 Receptor distribution in the CNS............................................................ 7 1.1.4.1 M1 receptors ................................................................................ 8 1.1.4.2 M2 receptors ................................................................................ 8 1.1.4.3 M3 receptors ................................................................................ 9 1.1.4.4 M4 receptors ................................................................................ 9 1.1.4.5 M5 receptors ................................................................................ 9 1.1.5 Non-neuronal ACh ............................................................................... 10 1.1.6 Muscarinic ligands ............................................................................... 11 1.1.6.1 Muscarinic agonists................................................................... 11 1.1.6.2 Non-selective antagonists ......................................................... 13 1.1.6.3 M1-selective antagonists............................................................ 13 1.1.6.4 M2-selective antagonists............................................................ 13 1.1.6.5 M3-selective antagonists............................................................ 14 1.1.6.6 M4-selective antagonists............................................................ 14 1.1.6.7 M5-selective antagonists............................................................ 14 1.1.7 Therapeutic options.............................................................................. 17 1.1.7.1 Peripheral tissues...................................................................... 17 1.1.7.2 Central nervous system............................................................. 18 1.1.8 Diagnostic potential.............................................................................. 20 1.2 Histamine receptors.......................................................................................... 20 1.2.1 H1-receptor distribution and function.................................................... 21 1.2.2 Ligands at H1 receptors........................................................................ 22 1.2.3 Therapeutic implications ...................................................................... 23 1.3 Serotonin receptors .......................................................................................... 24 1.3.1 5-HT3 receptors.................................................................................... 25 1.3.2 5-HT3-receptor distribution ................................................................... 28 1.3.3 Ligands at 5-HT3 receptors .................................................................. 28 1.3.4 Functional models................................................................................ 31 1.3.5 Therapeutic options.............................................................................. 31 1.3.5.1 Antiemetic properties................................................................. 31 1.3.5.2 Use in mental disorders............................................................. 32 1.3.5.3 Antinociceptive effects............................................................... 32 1.3.6 5-HT4 receptors.................................................................................... 33 I Table of Contents 1.3.7 5-HT4-receptor distribution ................................................................... 34 1.3.8 Ligands at 5-HT4 receptors .................................................................. 36 1.3.9 Functional models................................................................................ 37 1.3.10 Therapeutic options.............................................................................. 39 1.3.10.1 Cardiac arrhythmia .................................................................. 39 1.3.10.2 Urinary incontinence................................................................ 40 1.3.10.3 Cognition enhancement........................................................... 40 1.3.10.4 Gastrointestinal disorders........................................................ 40 1.4 Radioligand binding studies.............................................................................. 42 1.5 Recombinant receptor systems ........................................................................ 43 1.6 Stereochemistry ............................................................................................... 43 2 AIMS.................................................................................................................. 45 2.1 General considerations..................................................................................... 46 2.2 Analogues of ondansetron................................................................................ 46 2.3 Analogues of metoclopramide .......................................................................... 51 2.4 Analogues of McN-A-343 ................................................................................. 54 2.5 Analogues of glycopyrronium ........................................................................... 58 3 2.6 Characterisation of [ H](3R, 2’R)-glycopyrronium............................................. 63 2.7 M2-selective antagonists related to dimethindene ...........................................
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