Theoretical study of the interaction of agonists with the 5-HT_1tn2_1tnA receptor [Elektronische Ressource] / vorgelegt von Maria Elena Silva

Theoretical study of the interaction of
agonists with the 5-HT receptor 2A

Dissertation

zur Erlangung des Doktorgrades
der Naturwissenschaften (Dr. rer. nat)
der Fakultät für Chemie und Pharmazie
der Universität Regensburg



vorgelegt von
Maria Elena Silva
aus Buccinasco


Regensburg 2008
Die vorliegende Arbeit wurde in der Zeit von Oktober 2004 bis August 2008 an der
Fakultät für Chemie und Pharmazie der Universität Regensburg in der
Arbeitsgruppe von Prof. Dr. A. Buschauer unter der Leitung von Prof. Dr. S. Dove
angefertigt
















Die Arbeit wurde angeleitet von: Prof. Dr. S. Dove

Promotiongesucht eingereicht am: 28. Juli 2008

Promotionkolloquium am 26. August 2008

Prüfungsausschuß: Vorsitzender: Prof. Dr. A. Buschauer
1. Gutachter: Prof. Dr. S. Dove
2. Gutachter: Prof. Dr. S. Elz
3. Prüfer: Prof. Dr. H.-A. Wagenknecht

I
Contents
1 Introduction......................................................................................................... 1
1.1 G protein coupled receptors .....................................................................................1
1.1.1 GPCR classification ............................................................................................2
1.1.2 Signal transduction mechanisms in GPCRs .......................................................4
1.2 Serotonin (5-hydroxytryptamine, 5-HT) ....................................................................7
1.2.1 Historical overview..............................................................................................7
1.2.2 Biosynthesis and metabolism .............................................................................8
1.3 Serotonin receptors (5-HTR) ..................................................................................10
1.3.1 5-HTR classification..........................................................................................10
1.4 5-HT receptors (5-HT R) .......................................................................................13 2 2
1.4.1 5-HT receptor.................................................................................................14 2A
1.4.1.1 5-HT receptor structure............................................................................15 2A
1.4.1.2 5-HT R distribution, signal transduction and pharmacology......................18 2A
1.5 5-HT R agonists and antagonists .........................................................................20 2A
1.5.1 5-HT R agonists ..............................................................................................20 2A
1.5.1.1 Tryptamines ................................................................................................20
1.5.1.2 Phenylalkylamines ......................................................................................22
1.5.1.3 Quinazolinediones – a new partial agonistic structure................................24
1.5.2 5-HT R antagonists..........................................................................................25 2A
1.6 References .............................................................................................................28
2 Scope and Objective......................................................................................... 37
2.1 References40
3 Computational Methods ................................................................................... 41
3.1 GPCR homology models in medicinal chemistry....................................................41
3.2 Protein Database....................................................................................................43
3.3 Sequence alignment...............................................................................................44
3.4 3D structure generation ..........................................................................................44
3.5 Model validation......................................................................................................46
3.6 3D Quantitative Structure-Activity Relationships (3D QSAR).................................47
II
3.7 References .............................................................................................................50
4 Docking of representative partial agonists at 5-HT receptor models based 2A
on rhodopsin..................................................................................................... 53
4.1 Introduction...................................................................................................................53
4.2 Material and Methods..................................................................................................55
4.2.1 Model construction ................................................................................................55
4.2.2 Ligand selection, structure generation and docking ..............................................56
4.3 Results and Discussion58
4.3.1 5-HT receptor models.........................................................................................58 2A
4.3.2 Docking of representative partial agonists.............................................................59
4.4 Conclusion....................................................................................................................63
4.1 References .............................................................................................................65
5 5-HT receptor partial agonists: QSAR and interactions with the binding 2A
site...................................................................................................................... 69
5.1 Introduction69
5.2 The β adrenoceptor, a new template for GPCR homology modeling....................70 2
5.2.1 Crystal structures of the β adrenoceptor .........................................................70 2
5.2.2 Comparison of β AR and rhodopsin crystal structures .....................................72 2
5.3 Material and Methods .............................................................................................74
5.3.1 Data set.............................................................................................................74
5.3.2 Fragment Regression Analysis (FRA) ..............................................................75
5.3.3 Generation of 3D structure models of 5-HT receptors ...................................77 2A
5.3.4 Ligand selection, structure generation and docking..........................................78
5.3.5 3D QSAR Approaches: CoMFA and CoMSiA...................................................80
5.4 Results and Discussion ..........................................................................................81
5.4.1 Fragment Regression Analysis.........................................................................81
5.4.2 Comparison between 5-HT R models derived from β AR and from bovine 2A 2
rhodopsin ..........................................................................................................84
5.4.3 Docking of representative partial agonists........................................................87
5.4.4 3D-QSAR models .............................................................................................90
5.5 Conclusions ............................................................................................................98
5.6 References .............................................................................................................99
III
6 Modeling of the human 5-HT2A receptor in different active state and of
interaction with ligands.................................................................................. 103
6.1 Introduction...........................................................................................................103
6.2 Material and methods ...........................................................................................107
6.2.1 Model construction..........................................................................................107
6.2.2 Docking of 5-HT receptor agonists and partial agonists ..............................110 2A
6.3 Results..................................................................................................................111
6.3.1 Comparison of h5-HT R models in different states .......................................111 2A
6.3.2 Analysis of the fully active h5-HT R model in complex with 5-HT .................116 2A
6.3.3 he partially active h5-HT R model in complex with a partial agonist2A
........................................................................................................................117
6.4 Conclusions ..........................................................................................................120
6.5 References ...........................................................................................................121
7 Summary...................................................................Error! Bookmark not defined.
8 Appendix 129
8.1 Abbreviations............................................................................................