New, centrally acting dopaminergic agents with an improved oral bioavailability [2004]
.pdfNew, 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 |
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Introduction |
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1.1 |
Dopamine, a neurotransmitter in the central nervous system .............................................. |
1 |
1.2 |
General aspects of dopamine neurotransmission in the central nervous system.................. |
2 |
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1.2.1 Biosynthesis of dopamine ........................................................................................ |
2 |
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1.2.2 Dopamine re-uptake and metabolism ...................................................................... |
2 |
1.3 |
Dopamine receptors.............................................................................................................. |
4 |
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1.3.1 General structural features of G-protein-coupled receptors .................................... |
4 |
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1.3.2 Dopamine receptor classification............................................................................. |
5 |
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1.3.3 Dopamine D2 receptors............................................................................................ |
7 |
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1.3.4 Dopamine D3 receptors............................................................................................ |
9 |
1.4 |
Structure-activity relationships of dopamine receptor agonists ......................................... |
11 |
1.5 |
Pathogenesis of the dopaminergic system.......................................................................... |
15 |
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1.5.1 Parkinson’s disease ................................................................................................ |
16 |
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1.5.1.1 Pathology of Parkinson’s disease .............................................................. |
16 |
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1.5.1.2 Current treatment of Parkinson’s disease .................................................. |
18 |
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1.5.2 Schizophrenia......................................................................................................... |
20 |
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1.5.2.1 Pathology of schizophrenia ....................................................................... |
20 |
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1.5.2.2 Current treatment of schizophrenia ........................................................... |
21 |
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1.5.3 Drug abuse ............................................................................................................. |
23 |
1.6 |
Oral bioavailability of dopamine receptor agonists ........................................................... |
24 |
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1.6.1 Bioisosteric replacement........................................................................................ |
24 |
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1.6.2 Pro-drugs of dopamine receptor agonists .............................................................. |
25 |
1.7 Functional models used to study dopamine receptor ligands............................................. |
26 |
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1.7.1 Brain microdialysis ................................................................................................ |
26 |
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1.7.2 Locomotor activity in reserpinised rats ................................................................. |
26 |
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1.7.3 Behavioural characteristics in reserpinised rats..................................................... |
26 |
1.8 |
Scope of the thesis.............................................................................................................. |
27 |
Chapter 2................................................................................................................................. |
29 |
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Further characterisation of structural requirements for ligands at the |
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dopamine D2 and D3 receptor: studies with thienylethylamine as a |
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possible pharmacophore |
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2.1 |
Introduction ........................................................................................................................ |
30 |
2.2 |
Chemistry ........................................................................................................................... |
34 |
2.3 |
Results and discussion........................................................................................................ |
39 |
2.4 |
Experimental section .......................................................................................................... |
43 |
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2.4.1 Chemistry............................................................................................................... |
43 |
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2.4.2 Distance calculation............................................................................................... |
53 |
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2.4.3 Pharmacology ........................................................................................................ |
54 |
Chapter 3................................................................................................................................. |
57 |
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Studies with a series of 2-substituted tetrahydrobenzo[b]tiophenes as |
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dopamine receptor agents with selectivity for the dopamine D3 |
|
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receptor |
|
3.1 |
Introduction ........................................................................................................................ |
58 |
3.2 |
Chemistry ........................................................................................................................... |
59 |
3.3 |
Results and discussion........................................................................................................ |
60 |
3.4 |
Experimental section .......................................................................................................... |
63 |
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3.4.1 Chemistry............................................................................................................... |
63 |
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3.4.2 Pharmacology ........................................................................................................ |
65 |
Chapter 4................................................................................................................................. |
67 |
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Thiophene analogues of naphthoxazines and 2-aminotetralins: |
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bioisosteres with improved relative oral bioavailability, as compared |
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to 5-OH-DPAT |
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4.1 |
Introduction ........................................................................................................................ |
68 |
4.2 |
Materials and methods ....................................................................................................... |
72 |
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4.2.1 Animals .................................................................................................................. |
72 |
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4.2.2 Drug treatment ....................................................................................................... |
72 |
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4.2.3 Surgery and brain microdialysis ............................................................................ |
72 |
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4.2.4 Locomotor activity as monitored in automated cages and behavioural |
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characteristics......................................................................................................... |
73 |
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4.2.5 Statistics ................................................................................................................. |
73 |
4.3 |
Results ................................................................................................................................ |
74 |
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4.3.1 In vivo microdialysis .............................................................................................. |
74 |
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4.3.2 Locomotor activity in reserpinised rats ................................................................. |
79 |
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4.3.3 Behaviour in reserpinised rats................................................................................ |
80 |
4.4 |
Discussion .......................................................................................................................... |
81 |
Chapter 5................................................................................................................................. |
85 |
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Dopamine D2 activity of R-(–)-apomorphine and selected analogues: a |
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microdialysis study |
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5.1 |
Introduction ........................................................................................................................ |
86 |
5.2 |
Materials and methods ....................................................................................................... |
87 |
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5.2.1 Animals .................................................................................................................. |
87 |
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5.2.2 Drug treatment ....................................................................................................... |
88 |
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5.2.3 Surgery and brain microdialysis ............................................................................ |
88 |
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5.2.4 Data analysis .......................................................................................................... |
89 |
5.3 |
Results ................................................................................................................................ |
89 |
5.4 |
Discussion .......................................................................................................................... |
94 |
Chapter 6................................................................................................................................. |
97 |
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Neuropharmacological evaluation of a new dopaminergic prodrug |
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with anti-parkinsonian potential |
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6.1 |
Introduction ........................................................................................................................ |
98 |
6.2 |
Materials and methods ....................................................................................................... |
99 |
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6.2.1 Animals .................................................................................................................. |
99 |
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6.2.2 Drug treatment ....................................................................................................... |
99 |
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6.2.3 Surgery and brain microdialysis .......................................................................... |
100 |
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6.2.4 Statistics ............................................................................................................... |
101 |
6.3 |
Results .............................................................................................................................. |
101 |
6.4 |
Discussion ........................................................................................................................ |
105 |
Chapter 7............................................................................................................................... |
107 |
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References |
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Miscellaneous |
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Appendix ................................................................................................................................ |
125 |
Concluding remarks ............................................................................................................... |
129 |
Samenvatting.......................................................................................................................... |
133 |
List of Publications................................................................................................................. |
137 |
Posters and Abstracts ............................................................................................................. |
138 |
Dankwoord ............................................................................................................................. |
139 |