Drug design studies on selective dopamine receptor ligands:
Gespeichert in:
| 1. Verfasser: | |
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| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
2008
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| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | 172 S. graph. Darst. |
Internformat
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| 502 | |a Erlangen-Nürnberg, Univ., Diss., 2008 | ||
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Datensatz im Suchindex
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| adam_text | Contents
Contents:
1 Introduction 2
1.1 G Protein-Coupled Receptors (GPCRs) 2
1.2 Crystal structure of rhodopsin 3
1.3 Classification of GPCRs 4
1.4 Mechanism of signal transduction viaG-Proteins 5
1.5 The biological target. Dopamine receptors 6
1.6 The D3 receptor and D3 receptor ligands 8
1.7 Aim of the Thesis 13
2 CoMFA and CoMStA Investigations of Dopamine D3 Receptor ligands
Leading to the Prediction, Synthesis and Evaluation of Rigidized
FAUC 365 Analogues 15
2.1 Objective 15
2.2 Generation of structures and exploration of the conformational space 17
2.3 Alignment 22
2.4 CoMFA CoMSIA 23
2.5 Partial Least Squares (PLS)analysis 24
2.6 Results and discussion 25
2.6.1 CoMFA 25
2.6.2 CoMSIA 30
2.6.3 Advanced cross-validation and assessment of model predictivity 31
2.6.4 Graphical interpretation of the fields 34
2.6.4.1 CoMFA 34
2.6.4.2 CoMSIA 37
2.6.4.2.1 Steric contributions 38
2.6.4.2.2 Electrostatic contributions 39
2.6.4.2.3 Hydrophobic contributions 40
2.6.4.2.4 Hydrogen bond donor contributions 40
2.6.4.2.5 Hydrogen bond acceptor contributions 41
2.6.5 Prediction of novel, rigidized compounds 41
2.7 Biological Testing 43
2.8 Conclusion 44
Contents .
3 CoMFA and CoMSIA 3D-QSAR Analysis of D3 Receptor
Ligands Based on Docking Conformation 47
3.1 Objective 47
3.2 Methodology 48
3.3 Docking results 48
3.4 Graphical Comparison of the Preferential Binding Modes 49
3.5 CoMFA CoMSIA 51
3.6 Partial LeastSquares {PIS)analysis 51
3.7 Results and discussion 52
3.7.1 CoMFA 52
3.7.2 CoMSIA 54
3.7.3 Graphical interpretation of the fields 55
3.7.3.1 CoMFA 55
3.7.3.2 CoMSIA 58
3.7.3.2.1 Steric contributions 59
3.7.3.2.2 Electrostatic contributions 59
3.7.3.2.3 Hydrophobic contributions 60
3.7.3.2.4 Hydrogen bond donor contributions 60
3.7.3.2.5 Hydrogen bond acceptor contributions 61
3.8 Conclusion 61
4 St-ucture-Selectivity Investigations of D2-like Receptor Ugands by
CoMFA and CoMSIA Guiding the Discovery of D3 Selective PET
Radioligands 64
4.1 Objective 64
4.2 Results and Discussions 65
4.2.1 Assembly of the Training Set 65
4.2.2 Alignment 66
4.2.3 CoMFA 67
4.2.4 CoMSIA 69
4.2.5 Validation of the QSSR models 73
4.2.6 3D Contour Maps 76
4.2.0.1 Modnl:. lot Da/Dj, Siiuctlvlly / •
4.2.6.2 Models for D3/D, selectivity 79
Contents
4.2.7 Prediction of D3 Selective PET Tracers 82
4.3 Conclusion 83
4.4 Experimental Section 84
4.4.1 Structure Generation, Conformational Analysis and Alignment 84
4.4.2 CoMFA and CoMSIA 85
4.4.3 Partial Least Squares (PLS) analysis 87
5 Synthesis of Perphenazine and Haloperidol Dimers 89
5.1 Objective 89
5.2 Perphenazine dimers 91
5.3 Haloperidol dimers 98
5.4 Monomeric and dimeric esters of haloperidol 101
5.5 Haloperidol carbanalogs and carboxamide analogs 103
6 Summary 105
7 Zussamenfassung 112
8 Experimental Part 120
9 References 160
|
| adam_txt |
Contents
Contents:
1 Introduction 2
1.1 G Protein-Coupled Receptors (GPCRs) 2
1.2 Crystal structure of rhodopsin 3
1.3 Classification of GPCRs 4
1.4 Mechanism of signal transduction viaG-Proteins 5
1.5 The biological target. Dopamine receptors 6
1.6 The D3 receptor and D3 receptor ligands 8
1.7 Aim of the Thesis 13
2 CoMFA and CoMStA Investigations of Dopamine D3 Receptor ligands
Leading to the Prediction, Synthesis and Evaluation of Rigidized
FAUC 365 Analogues 15
2.1 Objective 15
2.2 Generation of structures and exploration of the conformational space 17
2.3 Alignment 22
2.4 CoMFA CoMSIA 23
2.5 Partial Least Squares (PLS)analysis 24
2.6 Results and discussion 25
2.6.1 CoMFA ' 25
2.6.2 CoMSIA 30
2.6.3 Advanced cross-validation and assessment of model predictivity 31
2.6.4 Graphical interpretation of the fields 34
2.6.4.1 CoMFA 34
2.6.4.2 CoMSIA 37
2.6.4.2.1 Steric contributions 38
2.6.4.2.2 Electrostatic contributions 39
2.6.4.2.3 Hydrophobic contributions 40
2.6.4.2.4 Hydrogen bond donor contributions 40
2.6.4.2.5 Hydrogen bond acceptor contributions 41
2.6.5 Prediction of novel, rigidized compounds 41
2.7 Biological Testing 43
2.8 Conclusion 44
Contents .
3 CoMFA and CoMSIA 3D-QSAR Analysis of D3 Receptor
Ligands Based on Docking Conformation 47
3.1 Objective 47
3.2 Methodology 48
3.3 Docking results 48
3.4 Graphical Comparison of the Preferential Binding Modes 49
3.5 CoMFA CoMSIA 51
3.6 Partial LeastSquares {PIS)analysis 51
3.7 Results and discussion 52
3.7.1 CoMFA 52
3.7.2 CoMSIA 54
3.7.3 Graphical interpretation of the fields 55
3.7.3.1 CoMFA 55
3.7.3.2 CoMSIA 58
3.7.3.2.1 Steric contributions 59
3.7.3.2.2 Electrostatic contributions 59
3.7.3.2.3 Hydrophobic contributions 60
3.7.3.2.4 Hydrogen bond donor contributions 60
3.7.3.2.5 Hydrogen bond acceptor contributions 61
3.8 Conclusion 61
4 St-ucture-Selectivity Investigations of D2-like Receptor Ugands by
CoMFA and CoMSIA Guiding the Discovery of D3 Selective PET
Radioligands 64
4.1 Objective 64
4.2 Results and Discussions 65
4.2.1 Assembly of the Training Set 65
4.2.2 Alignment 66
4.2.3 CoMFA 67
4.2.4 CoMSIA 69
4.2.5 Validation of the QSSR models 73
4.2.6 3D Contour Maps 76
4.2.0.1 Modnl:. lot Da/Dj, Siiuctlvlly / •
4.2.6.2 Models for D3/D, selectivity 79
Contents
4.2.7 Prediction of D3 Selective PET Tracers 82
4.3 Conclusion 83
4.4 Experimental Section 84
4.4.1 Structure Generation, Conformational Analysis and Alignment 84
4.4.2 CoMFA and CoMSIA 85
4.4.3 Partial Least Squares (PLS) analysis 87
5 Synthesis of Perphenazine and Haloperidol Dimers 89
5.1 Objective 89
5.2 Perphenazine dimers 91
5.3 Haloperidol dimers 98
5.4 Monomeric and dimeric esters of haloperidol 101
5.5 Haloperidol carbanalogs and carboxamide analogs 103
6 Summary 105
7 Zussamenfassung 112
8 Experimental Part 120
9 References 160 |
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| author | Salama, Ismail 1972- |
| author_GND | (DE-588)13404679X |
| author_facet | Salama, Ismail 1972- |
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| ctrlnum | (OCoLC)244031631 (DE-599)BVBBV023190779 |
| dewey-full | 615.19 |
| dewey-hundreds | 600 - Technology (Applied sciences) |
| dewey-ones | 615 - Pharmacology and therapeutics |
| dewey-raw | 615.19 |
| dewey-search | 615.19 |
| dewey-sort | 3615.19 |
| dewey-tens | 610 - Medicine and health |
| discipline | Medizin |
| discipline_str_mv | Medizin |
| format | Thesis Book |
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| illustrated | Illustrated |
| index_date | 2024-07-02T20:04:40Z |
| indexdate | 2024-07-09T21:12:41Z |
| institution | BVB |
| language | English |
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| spelling | Salama, Ismail 1972- Verfasser (DE-588)13404679X aut Drug design studies on selective dopamine receptor ligands von Ismail Salama 2008 172 S. graph. Darst. txt rdacontent n rdamedia nc rdacarrier Erlangen-Nürnberg, Univ., Diss., 2008 Ligand (DE-588)4035711-9 gnd rswk-swf Dopaminrezeptor (DE-588)4132055-4 gnd rswk-swf Selektivität (DE-588)4251340-6 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Dopaminrezeptor (DE-588)4132055-4 s Ligand (DE-588)4035711-9 s Selektivität (DE-588)4251340-6 s DE-604 HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016377177&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Salama, Ismail 1972- Drug design studies on selective dopamine receptor ligands Ligand (DE-588)4035711-9 gnd Dopaminrezeptor (DE-588)4132055-4 gnd Selektivität (DE-588)4251340-6 gnd |
| subject_GND | (DE-588)4035711-9 (DE-588)4132055-4 (DE-588)4251340-6 (DE-588)4113937-9 |
| title | Drug design studies on selective dopamine receptor ligands |
| title_auth | Drug design studies on selective dopamine receptor ligands |
| title_exact_search | Drug design studies on selective dopamine receptor ligands |
| title_exact_search_txtP | Drug design studies on selective dopamine receptor ligands |
| title_full | Drug design studies on selective dopamine receptor ligands von Ismail Salama |
| title_fullStr | Drug design studies on selective dopamine receptor ligands von Ismail Salama |
| title_full_unstemmed | Drug design studies on selective dopamine receptor ligands von Ismail Salama |
| title_short | Drug design studies on selective dopamine receptor ligands |
| title_sort | drug design studies on selective dopamine receptor ligands |
| topic | Ligand (DE-588)4035711-9 gnd Dopaminrezeptor (DE-588)4132055-4 gnd Selektivität (DE-588)4251340-6 gnd |
| topic_facet | Ligand Dopaminrezeptor Selektivität Hochschulschrift |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016377177&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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