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Pharmacological Study of KM822 Analogs---A Novel Class of Dopamine Transporter

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Pharmacological Study of KM822 Analogs---A Novel Class of Dopamine Transporter i ii Pharmacological Study of KM822 Analogs---a Novel Class of Dopamine Transporter Inhibitors By Xiaonan Liu June 2018 A Dissertation Presented to the Faculty of Drexel University College of Medicine in partial fulfillment of the Requirements for the Degree of Master iii DEDICATIONS I dedicate this thesis to my parents. iv ACKNOWLEDGEMENTS I would like to thank several people for supporting me and helping me in my thesis project. First, I would like to give utmost thanks to Dr. Ole Mortensen for accepting me in the lab, and offering me opportunities, and giving me advices in the project. He created a very nice and warm environment in the lab for me to explore in the science world. I would like to thank, Dr. Paul McGonigle, Dr. Joanne Mathiasen, Dr. Andreia Mortensen, and Dr. Ole Mortensen for agreeing to be a part of my thesis committee. Their guidance and feedback are very valuable for me not only for my thesis, but also for my career in the future. I would like to extend special thanks to Dr. Paul McGonigle, for being such a supportive director of Drug Discovery and Development program (DDD). I appreciate every advice and suggestion you had for me, and those are invaluable. And special thanks to Dr. Joanne Mathiasen, she is the co-director of DDD program, and the one making great effort to bridge China Pharmaceutical University with Pharmacology and Physiology department. I would also like to give special thanks to Dr. Andreia Mortensen, she provided me precious advices. I would like to thank Dr. Shaili Aggrawal for being such a patient teacher, she taught me techniques in detail, as well as providing advices in my data analysis. I would like to thank my friends in the lab, especially Stacia Lewandowski, Apeksha K, Caitlyn Rice, Stwarsti Sarks for willing to share my happiness and sadness. I would also like to thank my classmate and my friends in the department, especially for their help in and outside class. v Finally, I would like to thank my parents. They support my ideas and my endeavors both emotionally and financially. Without their encouragement and care, I would never go this far in my life. vi LIST OF ABBREVIATIONS BZT Benztropine CNS Central Nervous System DAT Dopamine Transporter dDAT Drosophila Dopamine Transporter DMSO Dimethyl Sulfoxide HSB Hybrid Structure Based LeuT Leucine Transporter MATs Monoamine Transporters MDCK Madin-Darby Canine Kidney NAc Nucleus Accumbens NET Norepinephrine Transporter NSS Neurotransmitter-sodium Symporter NTT Neurotransmitter Transporter PNS Peripheral Nervous System SAR Structure-activity Relationship SERT Serotonin Transporter SmDAT Schistosoma mansoni Dopamine Transporter SmNET Schistosoma mansoni Norepinephrine Transporter SLC6 Solute Carrier 6 TCA Tricyclic Antidepressant VMAT Vesicular Monoamine Transporter VTA Ventral Tegmental Area vii WT Wild Type 5-HT 5-hydroxytryptamine or Serotonin viii TABLE OF CONTENTS LIST OF FIGURES Figure 1. Schematic Depiction of Monoamine Transporters………………………….4 Figure 2. Model of the Conformation Cycle for Substrate Transport by the DAT...7 Figure 3. Chemical Structure, Chemical Formula and Molecular Weight of KM822…………………………………………………………………………………..13 Figure 4. Model of Human Dopamine Transporter (hDAT) highlighting the Allosteric Binding Pocket in the Complex with KM822 …………………………….14 Figure 5. Interaction between KM822 and W84 in the allosteric pocket…………...15 Figure 6. Dopamine Uptake Kinetics on Stable transfected MDCK hDAT Cells.…23 Figure 7. KM822 inhibits dopamine uptake in MDCK-hDAT and -hNET, and inhibits serotonin uptake in MDCK-hSERT cells…………………………………....25 Figure 8. Comparison of IC50 of KM822 in MATs…………………………………...25 Figure 9. KM822 Affects Cocaine Dose-response in hDAT, hNET and hSERT…...28 Figure 10. DA Uptake Kinetics in presence of several concentrations of KM822….29 Figure 11. Substitutions in KM822 Structure…………………….….……………….30 Figure 12. NP-1-145 Dose-response Curve……………………………………………31 Figure 13. NP-1-146 Dose-response Curve……………………………………………32 Figure 14. Dose-response Curves of NP-1-151 Series………………………………...34 Figure 15. Dose-response Curves of NP-1-154 Series………………………………...36 Figure 16. Dose-response Curves of NP-1-161 Series………………………………...39 Figure 17. NP-1-152 Affects Cocaine Dose-response in hDAT………………………42 Figure 18. NP-1-155 Affects Cocaine Dose-response in hDAT………………………43 ix Figure 19. NP-1-163 Affects Cocaine Dose-response in hDAT………………………44 Figure 20. NP-1-154 Affects Cocaine Dose-response in hDAT………………………45 Figure 21. NP-1-152 Affects Biotin Accessibility at W84…………………………….47 Figure 22. NP-1-155 Affects Biotin Accessibility at W84…………………………….49 Figure 23. NP-1-163 Affects Biotin Accessibility at W84…………………………….51 Figure 24. NP-1-154 Affects Biotin Accessibility at W84…………………………….53 LIST OF TABLES Table 1. Structures of KM822 and its analogs with substitutions indicated………..33 ABSTRACT………………………………………………………………………………………7 INTRODUCTION…………………………………………………………………………….…8 Monoamine Transporters……………………………………………………………….8 Dopamine Rewarding System and Cocaine Abuse…………………………………….9 Dopamine Transporter Structural Studies and Dopamine Uptake Cycle…………..11 Allosteric Modulation on Dopamine Transporter……………………………………13 Discovery of A Novel Allosteric Modulation Site on Dopamine Transporter………14 KM822—A Newly Identified Allosteric Modula for the Allosteric modulation.…...15 Studies on Amino Acid Residues Outlining the Novel Allosteric Modulation Site…16 Aims of Chemical Synthesis and Study of KM822 Analogs………………………….17 MATERIALS AND METHODS………………………………………………………………15 Generation of Cell Lines Stably Expressing Human DAT, NET and SERT……….19 Expression of DAT in Human Embryonic Kidney 293 (HEK293) Cells……………19 Dose-response Assays on analogs of KM822 Compounds …………………………..19 [3H]-Dopamine Uptake Kinetics Assays………………………………………………20 x Cocaine Dose-response Assays…………………………………………………………21 Biotinylation and Western Blot…………………………………………………….….22 RESULTS……………………………………………………………………………………….23 1. Optimization of Cell Number in 96-well Plates…………………………………….23 2. KM822 effect on dopamine transporter with or without cocaine………………...24 2.1. KM822 Inhibits All Three MATs…………………………………………24 2.2. KM822 Inhibits Cocaine’s Effect on hDAT, but not on hNET or hSERT…………………………………………………………………………...25 3. KM822 Decreases hDAT Dopamine Uptake Kinetics ……………….……………26 4. KM822 Analogs Display Varying Potencies in Inhibiting MATs ……….…….….29 4.1. NP-1-145 and NP-1-146 Dose-response Assays…………………………..31 4.2. NP-1-150, NP-1-151 and NP-1-152 Dose-response Assays………………32 4.3. NP-1-154 and NP-1-155 Dose-response Assays…………………………..35 4.4. NP-1-161, NP-1-162, NP-1-163 Dose-response Assays…………………..36 5. Selected compounds were screened in cocaine dose-response assays…………….40 5.1. NP-1-152 Affects Cocaine IC50 in hDAT..………………………………...41 5.2. NP-1-155 Affects Cocaine IC50 in hDAT………………………………….42 5.3. NP-1-163 Affects Cocaine IC50 in hDAT..………………………………...43 5.4. NP-1-154’s Effect on Cocaine IC50………………………………………..44 6. Selected Compounds Were Tested in Biotinylation Assays……………………….45 6.1. NP-1-152 Biotinylation Assays…………………………………………….46 6.2. NP-1-155 Biotinylation Assays…………………………………………….48 6.3. NP-1-163 Biotinylation Assays…………………………………………….50 xi 6.4. NP-1-154 Biotinylation Assays…………………………………………….52 DISCUSSION…………………………………………………………………………………...53 LIST OF REFERENCES…………...………………………………………………………….60 1 ABSTRACT The dopamine transporter (DAT) is a membrane protein that is responsible for the reuptake of dopamine back into the presynaptic neurons. DAT has been investigated intensively as a therapeutic target for substance abuse, depression, and attention deficit hyperactivity disorder. In the category of drugs of abuse, cocaine and other psychostimulants including amphetamine competitively inhibit all monoamine transporters, including dopamine transporter, norepinephrine transporter (NET) and serotonin transporter (SERT). By this mechanism, cocaine gives a sense of euphoria, and leads to dependency in the users. Chronic cocaine users have difficulty ceasing their cocaine abuse, and this leave cocaine addiction as a severe problem to the society. DAT has stood out to be a very promising target treating cocaine addiction. In a previous study, a region within the DAT has been found to modulate the transporter allosterically by comparing human dopamine transporter (hDAT) to a catecholamine transporter from Schistosoma mansoni. An allosteric site within hDAT was found based on the S. mansoni study using virtual screening, a small compound, called KM822, was identified. This compound was later shown to be binding at the predicted allosteric binding site in hDAT. Additionally, KM822 was shown to inhibit dopamine uptake and to inhibit cocaine binding to the transporter. Herein, we tested KM822 and KM822 analogs to investigate the structure-activity relationship between the transporter and these compounds. The overall goal of this project was to study the inhibitory properties of the KM822 class of compounds on dopamine uptake, as well as their effect on cocaine inhibition of DAT using cell-based functional assays. Also, we pursued to identify the structural characteristic that favors the interaction of these analogs with hDAT by 2 conducting biotinylation assays. Future in vivo studies will be performed by colleagues to investigate the effect of these compounds on cocaine mediated behaviors in rodent models. 3 INTRODUCTION 1. Monoamine Transporters Monoamine transporters (MATs) are members of the solute carrier 6 (SLC6) neurotransmitter transporter (NTT) family, which is also designated
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