GluN2B selective NMDA receptor antagonists: design, synthesis, pharmacological evaluation and docking studies
Gespeichert in:
| 1. Verfasser: | |
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| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
2015
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| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | 208 S. Ill., graph. Darst. |
Internformat
MARC
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| 100 | 1 | |a Gawaskar, Sandeep |d 1986- |e Verfasser |0 (DE-588)1067696202 |4 aut | |
| 245 | 1 | 0 | |a GluN2B selective NMDA receptor antagonists |b design, synthesis, pharmacological evaluation and docking studies |c vorgelegt von Sandeep Gawaskar |
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| 502 | |a Münster (Westfalen), Univ., Diss., 2015 | ||
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| 999 | |a oai:aleph.bib-bvb.de:BVB01-027934581 | ||
Datensatz im Suchindex
| _version_ | 1804153238060007424 |
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| adam_text | TABLE OF CONTENTS
1. INTRODUCTION 7
1.1. ALZHEIMER S DISEASE 7
1.1.1. ACETYLCHOLINESTERASE INHIBITORS 8
1.1.2. P-SECRETASE INHIBITORS 8
1.1.3. NMDA RECEPTOR ANTAGONISTS 9
1.2. NMDA RECEPTOR 10
1.2.1. GENERAL 10
1.2.2. STRUCTURE OF THE NMDA RECEPTOR 12
1.2.3. MODULATION OF THE NMDA RECEPTOR ACTIVITY 15
1.3. CONFORMATIONAL RESTRICTION 16
1.4. PREVIOUS WORK 18
1.4.1. TETRAHYDRO-3-BENZAZEPINES 18
1.4.2. BENZO[7]ANNULEN-7-AMINES 20
1.5. PHARMACOPHORE MODEL 21
2. AIM OF THE PROJECT 23
2.1. PROJECT DEVELOPMENT 23
2.2. SYNTHETIC PLAN 24
3. RECEPTOR BINDING STUDIES 26
3.1. PRINCIPLE 26
3.2. GLUN2B BINDING ASSAY 28
3.3. ASSAY FOR THE DETERMINATION OF THE AFFINITY TOWARDS THE PCP BINDING
SITE 28
3.4. AI AND OI BINDING ASSAYS 29
4. MOLECULAR MODELLING STUDIES 31
4.1. GENERAL 31
4.2. DOCKING PROTOCOL 31
4.3. DOCKING VALIDATION 33
5. PART 1: BENZO[7]ANNULEN-7-AMINES WITHOUT FURTHER SUBSTITUENTS 34
5.1. SYNTHESIS 34
5.1.1. SYNTHESIS OF THE KETONE 28 34
5.1.2. REDUCTIVE AMINATION OF 28 38
5.1.3. SN2 REACTION TO GENERATE TERTIARY AMINES 29E-G 41
5.1.4. SYNTHESIS OF DIASTEREOMERIC AMINES C/S-29H AND TRANS-29I 46
3
HTTP://D-NB.INFO/1068085436
5.2. RECEPTOR AFFINITY OF AMINES 29A-I 52
5.2.1. AFFINITY TOWARDS GLUN2B CONTAINING NMDA RECEPTORS 52
5.2.2. AFFINITY TOWARDS OTHER RECEPTORS 54
5.3. DOCKING STUDY OF PHENYLPROPYL AMINE 29C 56
6. PART 2: BENZO[7]ANNULEN-7AMINES WITH DIFFERENT SUBSTITUENTS IN 2-
POSITION 58
6.1. SYNTHESIS 58
6.1.1. SYNTHESIS OF 2-NITROBENZO[7]ANNULEN-7-ONE 30 58
6.1.2. BENZO[7]ANNULEN-7-AMINES 32A-F WITH A NO2 GROUP IN 2-POSITION 60
6.1.3. ATTEMPTS TO INTRODUCE A HYDROXYL MOIETY IN BENZYL POSITION OF 30
62
6.1.4. BENZO[7]ANNULEN-7-AMINES 62A-E WITH AN AMINO MOIETY IN 2-
POSITION 64
6.1.5. BENZO[7]ANNULEN-7-AMINES WITH AN ACETYLAMINO AND A
SULFONYLAMINO MOIETY IN 2-POSITION 66
6.1.6. BENZO[7]ANNULEN-7AMINES WITH HYDROXY AND ALKOXY MOIETIES IN 2-
POSITION 68
6.1.7. FURTHER VARIATIONS OF THE 2-SUBSTITUENT VIA DIAZONIUM SALTS 74
6.1.8. SYNTHESIS OF AZO COMPOUND 80 76
6.2. RECEPTOR AFFINITY OF 2-SUBSTITUTED BENZO[7]ANNULEN-7-AMINES 78
6.2.1. 2-NITROBENZO[7]ANNULEN-7-AMINES 32A-F 78
6.2.2. 2-SUBSTITUTED BENZO[7]ANNULEN-7-AMINES 79
6.2.3. OPTIMAL N-PHENYL DISTANCE 82
6.2.3.1. GLUN2B AFFINITY 82
6.2.3.2. SELECTIVITY OF THE 2-BENZYLOXY DERIVATIVE 71 A 84
6.2.4. 2-AMINO AND 2-HYDROXYBENZO[7]ANNULEN-7-AMINES, 62A-E AND 68A-C.
86
6.2.5. CONFORMATIONAL^ RESTRICTED 2-BENZYLOXY DERIVATIVE 71 C 88
6.3. DOCKING STUDY OF AMINES 32C AND 71A 89
7. PART 3: VARIATION OF THE CARBOCYCLIC RING SIZE 92
7.1. SYNTHESIS 92
7.1.1. CONCEPT FOR THE SYNTHESIS OF TETRALIN-2-AMINES 24 92
7.1.2. SYNTHESIS OF TETRALIN-2-AMINES 24A-D 93
7.1.3. SYNTHESIS OF TETRALIN-2-AMINES 24E-F BY NUCLEOPHILIC SUBSTITUTION
94
7.1.4. CONCEPT FOR THE SYNTHESIS OF INDAN-2-AMINES 25 94
7.1.5. SYNTHESIS INDAN-2-AMINES 25A AND 25B BY REDUCTIVE AMINATION OF
KETONE 35 95
7.1.6. SYNTHESIS OF INDAN-2-AMINES 25C-F BY NUCLEOPHILIC SUBSTITUTION 97
7.2. RECEPTOR AFFINITY OF TETRALIN-2-AMINES 24A-F AND INDAN-2-AMINES
25A-
F 99
4
7.2.1. DISCUSSION OF GLUN2B AFFINITY 100
7.2.2. DISCUSSION OF THE AFFINITY TOWARDS 01 AND 02 RECEPTORS 101
8. SUMMARY 102
8.1. PART 1: UNSUBSTITUTED BENZO[7]ANNULEN-7-AMINES 102
8.2. PART 2: 2-SUBSTITUTED BENZO[7]ANNULEN-7-AMINES 104
8.3. PART 3: VARIATION OF THE CARBOCYCLIC RING SIZE 107
9. EXPERIMENTAL PART 109
9.1. GENERAL METHODS 109
9.1.1. GENERAL WORKING TECHNIQUES 109
9.1.2. SOLVENTS 109
9.1.3. THIN LAYER CHROMATOGRAPHY 109
9.1.4. FLASH CHROMATOGRAPHY 110
9.1.5. ANALYTICAL HPLC 110
9.1.6. NMR SPECTROSCOPY 111
9.1.7. MASS SPECTROSCOPY 113
9.1.8. INFRARED SPECTROSCOPY 113
9.1.9. MELTING POINTS 113
9.2. MOLECULAR MODELING 113
9.2.1. STOCHASTIC CONFORMATIONAL SEARCH 113
9.2.2. DOCKING STUDIES 114
9.3. SYNTHETIC PROCEDURES 115
10. RECEPTOR BINDING STUDIES 181
11. BIBLIOGRAPHY 186
12. APPENDICES 194
12.1. CONFORMATIONAL ANALYSIS 194
12.2. LIST OF FIGURES 195
12.3. LIST OF TABLES 197
12.4. LIST OF SCHEMES 198
12.5. LIST OF ACRONYMS 200
12.6. COMPOUND LIST 202
13. CURRICULUM VITAE 208
5
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| spelling | Gawaskar, Sandeep 1986- Verfasser (DE-588)1067696202 aut GluN2B selective NMDA receptor antagonists design, synthesis, pharmacological evaluation and docking studies vorgelegt von Sandeep Gawaskar 2015 208 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Münster (Westfalen), Univ., Diss., 2015 (DE-588)4113937-9 Hochschulschrift gnd-content DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027934581&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Gawaskar, Sandeep 1986- GluN2B selective NMDA receptor antagonists design, synthesis, pharmacological evaluation and docking studies |
| subject_GND | (DE-588)4113937-9 |
| title | GluN2B selective NMDA receptor antagonists design, synthesis, pharmacological evaluation and docking studies |
| title_auth | GluN2B selective NMDA receptor antagonists design, synthesis, pharmacological evaluation and docking studies |
| title_exact_search | GluN2B selective NMDA receptor antagonists design, synthesis, pharmacological evaluation and docking studies |
| title_full | GluN2B selective NMDA receptor antagonists design, synthesis, pharmacological evaluation and docking studies vorgelegt von Sandeep Gawaskar |
| title_fullStr | GluN2B selective NMDA receptor antagonists design, synthesis, pharmacological evaluation and docking studies vorgelegt von Sandeep Gawaskar |
| title_full_unstemmed | GluN2B selective NMDA receptor antagonists design, synthesis, pharmacological evaluation and docking studies vorgelegt von Sandeep Gawaskar |
| title_short | GluN2B selective NMDA receptor antagonists |
| title_sort | glun2b selective nmda receptor antagonists design synthesis pharmacological evaluation and docking studies |
| title_sub | design, synthesis, pharmacological evaluation and docking studies |
| topic_facet | Hochschulschrift |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027934581&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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