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New, centrally acting dopaminergic agents with an improved oral bioavailability [2004]

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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 D2 receptors............................................................................................

7

 

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

 

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 D2 and D3 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 D3

 

 

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 D2 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