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Target Profiles at Adenosine A2aand Dopamine D2

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Target Profiles at Adenosine A2aand Dopamine D2 DISCOVERY OF INDOLYL PIPERAZINYLPYRIMIDINES WITH DUAL- TARGET PROFILES AT ADENOSINE A2A AND DOPAMINE D2 RECEPTORS FOR PD TREATMENT SHAO YI-MING (B. Sc. and M. Sc., National Taiwan University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY NUS GRADUATE SCHOOL FOR INTEGRATIVE SCIENCES AND ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2014 ACKNOWLEDGEMENTS I would like to extend sincere gratitude to my supervisor, A/Prof. Giorgia PASTORIN, for giving me an opportunity to do my Ph.D. in her laboratory. I still can clearly remember how flexible and agreeable she was to my proposals on polypharmacology when I first approached her in December of 2010. It was the freedom to pursue new ideas, such as A2A/D2 polypharmacology, offered by her that impressed me and made me decide to join her laboratory. Over the years, she has been showing enthusiasm by allocating funds, time, energy and manpower to my projects. In addition, her qualities of wisdom, modesty and considerateness have been, and will continue to be, my inspiration. I deem it an honour and a rare privilege to work with her during my Ph.D. studies. I am also grateful to my Thesis Advisory Committee, Prof. CHEN Yu Zong and Prof. Giampiero SPALLUTO, for their constant advices with regard to my projects. I especially thank Prof. Chen’s support and suggestions at the initial stage of A2A/D2 project. Moreover, I am appreciative of my thesis examiners, Prof. GO Mei Lin and Prof. Brian DYMOCK, for their valuable comments on the thesis. My appreciation also goes to Dr. Priyankar PAIRA for his guidance in organic synthesis, Dr. MA Xiaohua for computer modeling, Prof. Karl-Norbert KLOTZ for radioligand assays, Dr. ANG Wee Han and Miss TAN Geok Kheng for X- ray crystallographic analysis, Madam WONG Lai Kwai for high resolution mass spectrometry analysis, Dr. Sourabh BANERJEE and Dr. Madhavan NALLANI for artificial cell membrane assays, Miss WANG Wei and Dr. Deron HERR for functional assays, NUS Drug Development Unit for assays on drug- ii ACKNOWLEDGEMENTS like properties and prior art search, Dr. NG Chee Hoe and A/Prof. LIM Kah- Leong for Drosophila experiments, Mr. YANG Xuan, Dr. Sam RAMANUJULU and Mr. SEE Cheng Shang for assistance in high-performance liquid chromatography, all members in Giorgia’s group and all people in S15 Level 5 for day-to-day operations, NGS for scholarship, as well as NUS Pharmacy Department for research facilities. I am thankful for my brothers in Christ, Miss Esther TAN, NUS Office of Safety, Health & Environment, as well as my family members for their care and concern. iii TABLE OF CONTENTS DECLARATION............................................................................................... i ACKNOWLEDGEMENTS ............................................................................ ii TABLE OF CONTENTS ............................................................................... iv SUMMARY ................................................................................................... viii LIST OF TABLES .......................................................................................... ix LIST OF FIGURES ........................................................................................ xi LIST OF SCHEMES .................................................................................. xviii LIST OF ABBREVIATIONS ...................................................................... xix CHAPTER 1 PARKINSON’S DISEASE (PD) ........................................... 1 1.1 Introduction to PD ................................................................................. 1 1.2 Current PD Pharmacotherapeutics ........................................................ 7 1.2.1 Dopamine replacement therapies ................................................... 7 1.2.2 Non-dopaminergic therapies ........................................................ 10 1.3 Opportunities of Polypharmacology in Treating PD ........................... 12 1.3.1 Approaches to multi-targeting ...................................................... 12 1.3.2 Polypharmacology in PD .............................................................. 24 1.3.2.1 An example: MAO-B inhibitor + A2A antagonist ................. 24 1.3.2.2 An opportunity: D2 agonist + A2A antagonist ....................... 31 1.4 Chapter Conclusion ............................................................................. 35 CHAPTER 2 HYPOTHESIS AND AIMS ................................................. 36 CHAPTER 3 LIGAND-BASED VIRTUAL SCREENING AND ANALYSES ...................................................................................................... 40 3.1 Receptor Agonism and Antagonism ................................................... 40 3.1.1 Preclinical studies on two-drug cocktail (KW-6002 + a D2 agonist) .................................................................................................................. 42 3.1.2 Compounds capable of agonising one receptor but antagonising another ...................................................................................................... 43 iv TABLE OF CONTENTS 3.1.3 Compounds capable of agonising D2 receptor but antagonising A2A receptor .............................................................................................. 45 3.1.3.1 Comparison between A2A agonism and antagonism ............ 47 3.1.3.2 Comparison between D2 agonism and antagonism ............... 51 3.2 Support Vector Machine Models ........................................................ 54 3.2.1 Introduction .................................................................................. 55 3.2.2 Methods ........................................................................................ 56 3.2.2.1 Molecular descriptors............................................................ 56 3.2.2.2 Generation of putative inactive compounds ......................... 58 3.2.2.3 Support vector machine classification .................................. 58 3.2.2.4 Model validation ................................................................... 62 3.2.3 Results and discussion .................................................................. 64 3.2.3.1 Collection of adenosine A2A receptor antagonists ................ 64 3.2.3.2 Collection of dopamine D2 receptor agonists ....................... 65 3.2.3.3 N-arylpiperazine—a privileged substructure ........................ 68 3.2.3.4 Generation of putative inactive compounds ......................... 71 3.2.3.5 Establishment of SVM models for virtual screening ............ 74 3.3 Tanimoto Similarity ............................................................................ 85 3.3.1 Introduction .................................................................................. 85 3.3.2 Methods ........................................................................................ 87 3.3.3 Results and discussion .................................................................. 87 3.4 Chapter Conclusion ............................................................................. 93 CHAPTER 4 DESIGN, SYNTHESIS, AND A2A RECEPTOR BINDING STUDIES OF INDOLYL PIPERAZINYLPYRIMIDINES .... 94 4.1 Design Rationale ................................................................................. 94 4.2 IPP ..................................................................................................... 110 4.2.1 Chemical considerations ............................................................. 110 4.2.2 Experimental methods ................................................................ 113 4.2.3 Results and discussion ................................................................ 125 4.3 Indole C4~C7 Positions of IPP ......................................................... 127 4.3.1 Chemical considerations ............................................................. 127 4.3.2 Experimental methods ................................................................ 128 4.3.3 Results and discussion ................................................................ 136 4.4 Indole C2 Position of IPP .................................................................. 141 v TABLE OF CONTENTS 4.4.1 Chemical considerations ............................................................. 141 4.4.2 Experimental methods ................................................................ 144 4.4.3 Results and discussion ................................................................ 151 4.5 Chapter Conclusion ........................................................................... 154 CHAPTER 5 FURTHER PHARMACOLOGICAL EVALUATION AND CHARACTERISATION OF COMPOUNDS 69 AND 70 .............. 156 5.1 Introduction ....................................................................................... 156 5.2 Materials and Methods ...................................................................... 158 5.3 Results and Discussion ...................................................................... 165 5.3.1 Proteopolymersomes for D2 receptor binding assay .................. 165 5.3.2 Cell-based functional assay for D2 receptor ............................... 170 5.3.3 Drug-like properties .................................................................... 184 5.3.3.1 Solubility and permeability assays...................................... 188 5.3.3.2 Metabolism assays .............................................................. 195 5.3.3.3 Toxicity assays ...................................................................
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