Novel agonists and potent antagonists at P2Y_1tn1_1tn1 purinergic receptors: synthesis and biological testing [Elektronische Ressource] = Neue Agonisten und potente Antagonisten an P2Y_1tn1_1tn1-Purinergic-Rezeptoren: Synthese und biologische Untersuchung / vorgelegt von Sophi Damayanti

Bayu

Sujets

• Gesundheit

Informations

• Publié par: heinrich-heine-universitat_dusseldorf
• Publié le: 01 janvier 2008
• Nombre de lectures: 24
• Langue: Deutsch
• Poids de l'ouvrage: 2 Mo

Extrait

Novel Agonists and Potent Antagonists
at P2Y Purinergic Receptors: 11
Synthesis and Biological Testing


Neue Agonisten und potente Antagonisten
an P2Y Purinergen Rezeptoren: 11
Synthese und Biologische Untersuchung






Inaugural-Dissertation
zur
Erlangung des Doktorgrades
der Mathematisch-Naturwissenschaftlichen Fakultät
der Heinrich-Heine-Universität Düsseldorf










vorgelegt von
Sophi Damayanti
aus Bandung, Indonesien




Düsseldorf, 2008



Aus dem Institut für Pharmazeutische und Medizinische Chemie
der Heinrich-Heine-Universität-Düsseldorf

„Gedruckt mit Unterstützung der Islamic Development Bank (IDB)“
































Gedruckt mit der Genehmigung
der Mathematisch-Naturwissenschaftlichen Fakultät
der Heinrich-Heine-Universität Düsseldorf

Referent: Prof. Dr. Matthias U. Kassack
Koreferent: Prof. Dr. Thomas Kurz

Tag der mündlichen Prüfung: 26.11.2008





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Erklärung

Ehrenwörtlich erkläre ich hiermit, dass ich die vorgelegte Dissertation mit dem
Titel: “Novel agonists and potent antagonists at P2Y purinergic receptors: 11
Synthesis and biological testing” selbst angefertigt und ohne fremde Hilfe
verfasst habe. Quellen und Hilfsmittel sind vollständig angegeben. Weiterhin
erkläre ich, dass ich bisher keine erfolglosen Promotionsversuche
unternommen habe.


Düsseldorf, 27.10.2008
Sophi Damayanti
































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For my husband and my parents

I am truly blessed

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LIST OF CONTENTS

1. INTRODUCTION .............................................................. 1
1.1. Purinergic receptors................................................................................ 1
1.1.1. General aspects ........................................................................... 1
1.1.2. P2X receptors............................................................................... 2
1.1.2.1. Role and location ............................................................ 2
1.1.2.2. Ligands at P2X receptors................................................ 4
1.1.3. P2Y receptors 6
1.1.3.1. G protein-coupled receptors............................................ 6
1.1.3.2. Location and role of P2Y receptors................................. 8
1.1.3.3. Ligands at P2Y receptors.............................................. 10
1.2. P2Y receptors..................................................................................... 15 11
1.2.1. General aspects ......................................................................... 15
1.2.2. Role of P2Y receptors.............................................................. 15 11
1.2.3. Ligands at P2Y receptors......................................................... 16 11
2. AIM AND SCOPE OF THE STUDY................................ 19
2.1. Synthesis of novel ligands..................................................................... 19
2.1.1. Synthesis of urea derivatives containing trisodium 7-
naphthalene-1,3,5-trisulfonate substituent and 4-fluoro -3,1-
phenylene-linker......................................................................... 19
2.1.2. Synthesis of urea derivatives containing trisodium 3-(2,4-
disulfonatophenylcarbamoyl)benzoate substituent..................... 21
2.2. Biological evaluation ............................................................................. 21
3. CHEMISTRY................................................................... 22
3.1. Synthesis of urea derivatives containing trisodium 7-naphthalene-
1,3,5-trisulfonate substituent ................................................................. 22
3.1.1. Synthesis of “small urea” derivatives.......................................... 24
3.1.1.1. Trisodium 7-(4-fluoro-3-nitrobenzamido)-naphthalene-
1,3,5-trisulfonate ........................................................... 24
3.1.1.2. Trisodium 7-(3-amino-4-fluorobenzamido)-
naphthalene-1,3,5-trisulfonate ...................................... 33
3.1.1.3. Hexasodium 7,7’- carbonylbis[azanediyl(4-fluoro-3,1-
phenylene) carbonylazanediyl] bis(naphthalene-1,3,5-
trisulfonate) ................................................................... 40
3.1.2. Synthesis of “large urea” derivatives .......................................... 47
3.1.2.1. Trisodium 7-[4-(3-nitrobenzamido)-benzamido]-
naphthalene-1,3,5-trisulfonate ...................................... 47
3.1.2.2. Trisodium 7-[4-(3-aminobenzamido)-benzamido]-isulfonate 50
3.1.2.3. Hexasodium 7,7 - carbonylbis[azanediyl-3,1-
phenylene carbonylazanediyl(4,1-
phenylene)carbonylazl] bis(naphthalene-1,3,5-
trisulfonate) ................................................................... 53
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3.2. Synthesis of urea derivatives containing 4-fluoro-3,1- phenylene-
linker at benzene or naphthalene sulfonates .........................................57
3.2.1. Disodium 2-(4-fluoro-3-nitrobenzamido)benzene-1,4-
disulfonate ..................................................................................58
3.2.2. Disodium 2-(3-amino-4-fluorobenzamido)benzene-1,4-
disulfonate64
3.2.3. Tetrasodium 2,2'- carbonylbis[azanediyl(4-fluoro-3,1-
phenylene)carbonylazanediyl] bis(benzene-1,4-disulfonate) .....69
3.3. Synthesis of urea derivatives containing trisodium 3-(2,4-
disulfonatophenylcarbamoyl)benzoate substituent................................75
3.3.1. Trisodium 3-(2,4-disulfonatophenylcarbamoyl)-5-(4-
nitrobenzamido)benzoate ...........................................................77
3.3.2. l)-5-(4-
aminobenzamido)benzoate.........................................................81
3.3.3. Hexasodium 5,5 -[carbonylbis(azanedyl-4,1-
phenylenecarbonylazanediyl]bis[3-(2,4-
disulfonatophenylcarbamoyl)benzoat] ........................................84
4. PHARMACOLOGY89
4.1. Evaluation of the test system.................................................................89
4.2. Agonist screening of compounds at P2Y receptors ............................91 11
4.2.1. Primary agonist screening of compounds at P2Y receptors.....91 11
4.2.2. Efficacy and potency testing .......................................................94
4.2.3. Concentration-response curves of compounds 8c and 9c ..........96
4.2.4. Schild analysis of compound 9c..................................................99
4.3. Antagonist screening at P2Y receptors .............................................101 11
4.4. Urea derivatives containing trisodium 7-naphthalene-1,3,5-trisulfonate
substituent ...........................................................................................107
4.4.1. Apparent pK value of urea 1c -14c...........................................107 i
4.4.2. Schild analysis of compound 5c................................................117
4.5. Urea derivatives containing 4-fluoro-3,1-phenylene-linker...................118
4.6. Urea derivatives containing trisodium 3(2,4-
disulfonatophenylcarbamoyl)benzoate su