University of Groningen New, centrally acting dopaminergic agents with an improved oral bioavailability Rodenhuis, Nieske IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2000 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Rodenhuis, N. (2000). New, centrally acting dopaminergic agents with an improved oral bioavailability: synthesis and pharmacological evaluation. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 08-03-2019
New, centrally acting dopaminergic agents with an improved oral bioavailability: synthesis and pharmacological evaluation
RIJKSUNIVERSITEIT GRONINGEN New, centrally acting dopaminergic agents with an improved oral bioavailability: synthesis and pharmacological evaluation PROEFSCHRIFT ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. D.F.J. Bosscher, in het openbaar te verdedigen op maandag 23 oktober 2000 om 16.00 uur door Nieske Rodenhuis geboren op 30 september 1971 te Oosterlittens
Promotor Prof. Dr. H.V. Wikström Referent Dr. D. Dijkstra
Foar Heit en Mem en Kor-Marten
Promotiecommissie Prof. Dr. D. Nichols Prof. Dr. A.P. IJzerman Prof. Dr. T. Svensson Paranimfen Klaas Rodenhuis Jan Rodenhuis Colophon Copyright 2000 by N. Rodenhuis. All rights reserved. No part of this book may be reproduced in any manner or by any means without written permission from the publisher An electronic version of this thesis is available at http://www.ub.rug.nl/eldoc/dis/science/n.rodenhuis ISBN 90-367-1279-3 NUGI 746 Printing: PrintPartners Ipskamp BV, Enschede, The Netherlands Cover design: N. Rodenhuis en K.-M. Lok The research project described in this thesis was performed within the framework of the research school GUIDE.
Contents Chapter 1... 1 Introduction 1.1 Dopamine, a neurotransmitter in the central nervous system... 1 1.2 General aspects of dopamine neurotransmission in the central nervous system... 2 1.2.1 Biosynthesis of dopamine... 2 1.2.2 Dopamine re-uptake and metabolism... 2 1.3 Dopamine receptors... 4 1.3.1 General structural features of G-protein-coupled receptors... 4 1.3.2 Dopamine receptor classification... 5 1.3.3 Dopamine D 2 receptors... 7 1.3.4 Dopamine D 3 receptors... 9 1.4 Structure-activity relationships of dopamine receptor agonists... 11 1.5 Pathogenesis of the dopaminergic system... 15 1.5.1 Parkinson s disease... 16 1.5.1.1 Pathology of Parkinson s disease... 16 1.5.1.2 Current treatment of Parkinson s disease... 18 1.5.2 Schizophrenia... 20 1.5.2.1 Pathology of schizophrenia... 20 1.5.2.2 Current treatment of schizophrenia... 21 1.5.3 Drug abuse... 23 1.6 Oral bioavailability of dopamine receptor agonists... 24 1.6.1 Bioisosteric replacement... 24 1.6.2 Pro-drugs of dopamine receptor agonists... 25 1.7 Functional models used to study dopamine receptor ligands... 26 1.7.1 Brain microdialysis... 26 1.7.2 Locomotor activity in reserpinised rats... 26 1.7.3 Behavioural characteristics in reserpinised rats... 26 1.8 Scope of the thesis... 27 Chapter 2... 29 Further characterisation of structural requirements for ligands at the dopamine D 2 and D 3 receptor: studies with thienylethylamine as a possible pharmacophore
2.1 Introduction... 30 2.2 Chemistry... 34 2.3 Results and discussion... 39 2.4 Experimental section... 43 2.4.1 Chemistry... 43 2.4.2 Distance calculation... 53 2.4.3 Pharmacology... 54 Chapter 3... 57 Studies with a series of 2-substituted tetrahydrobenzo[b]tiophenes as dopamine receptor agents with selectivity for the dopamine D 3 receptor 3.1 Introduction... 58 3.2 Chemistry... 59 3.3 Results and discussion... 60 3.4 Experimental section... 63 3.4.1 Chemistry... 63 3.4.2 Pharmacology... 65 Chapter 4... 67 Thiophene analogues of naphthoxazines and 2-aminotetralins: bioisosteres with improved relative oral bioavailability, as compared to 5-OH-DPAT 4.1 Introduction... 68 4.2 Materials and methods...72 4.2.1 Animals... 72 4.2.2 Drug treatment... 72 4.2.3 Surgery and brain microdialysis... 72 4.2.4 Locomotor activity as monitored in automated cages and behavioural characteristics... 73 4.2.5 Statistics... 73 4.3 Results... 74 4.3.1 In vivo microdialysis... 74 4.3.2 Locomotor activity in reserpinised rats... 79
4.3.3 Behaviour in reserpinised rats... 80 4.4 Discussion... 81 Chapter 5... 85 Dopamine D 2 activity of R-( )-apomorphine and selected analogues: a microdialysis study 5.1 Introduction... 86 5.2 Materials and methods...87 5.2.1 Animals... 87 5.2.2 Drug treatment... 88 5.2.3 Surgery and brain microdialysis... 88 5.2.4 Data analysis... 89 5.3 Results... 89 5.4 Discussion... 94 Chapter 6... 97 Neuropharmacological evaluation of a new dopaminergic prodrug with anti-parkinsonian potential 6.1 Introduction... 98 6.2 Materials and methods...99 6.2.1 Animals... 99 6.2.2 Drug treatment... 99 6.2.3 Surgery and brain microdialysis... 100 6.2.4 Statistics... 101 6.3 Results... 101 6.4 Discussion... 105 Chapter 7... 107 References Miscellaneous Appendix... 125 Concluding remarks... 129
Samenvatting... 133 List of Publications... 137 Posters and Abstracts... 138 Dankwoord... 139