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I Chemical Biology Approaches to Combat Parkinson's Disease By Chemical Biology Approaches to Combat Parkinson’s Disease by Felix O. Nwogbo Jr Department of Chemistry Duke University Date: _______________________ Approved: ___________________________ Dewey G. McCafferty, Supervisor ___________________________ Jennifer L. Roizen ___________________________ Jiyong Hong ___________________________ David M. Gooden Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2018 i v ABSTRACT Chemical Biology Approaches to Combat Parkinson’s Disease by Felix O. Nwogbo Jr Department of Chemistry Duke University Date: _______________________ Approved: ___________________________ Dewey G. McCafferty, Supervisor ___________________________ Jennifer L. Roizen ___________________________ Jiyong Hong ___________________________ David M. Gooden An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2018 i v Copyright by Felix O. Nwogbo Jr 2018 Abstract Parkinson's disease (PD) is a debilitating neurodegenerative disease of the central nervous system characterized by loss of striatal dopaminergic projections from the substantia nigra. Although there is no cure for PD, dopamine (DA) replacement using L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common therapy used to manage PD motor symptoms. L-DOPA is poorly absorbed into the brain and metabolized in the periphery causing its efficacy to wane over time. Additionally, within five years of use, L-DOPA can induce its own severe motor dysfunction, such as dyskinesias, which can be irreversible. This underscores the need for the discovery and development of improved anti-Parkinsonian therapeutics. We have identified a class of conformationally-constrained phenylethylamines based on a tranylcypromine scaffold and demonstrated that many compounds in this structural class exhibited partial or full relief of akinesia in a DA-deficient/DA transporter knockout (DAT-KO) mouse model of PD developed in the Caron laboratory. Two active arylcyclopropylamines from studies in DAT-KO mice were subsequently evaluated in a 6-hydroxydopamine-lesioned rat model to confirm their anti-Parkinsonian and anti-dyskinesia activities. In these rats, both compounds improved lesioned-induced motor deficits that mimic PD-associated akinesia. Target identification and activity assays suggest 5-HT2B and a2A as candidate targets to begin elucidation of novel non-dopaminergic pathways to combat PD. iv Dedication Simply and sincerely, I dedicate this dissertation to my family and friends who supported my journey to this point and undoubtedly will continue to do so for years to come. Your love and unwavering support have helped me through one of the most challenging experiences I have had—this would not be possible without each and every one of you. v Contents Abstract .......................................................................................................................................... iv List of Tables .................................................................................................................................. x List of Figures ............................................................................................................................... xi List of Schemes ........................................................................................................................... xvi List of Abbreviations ................................................................................................................ xvii Acknowledgements ................................................................................................................. xxiv 1. Introduction ............................................................................................................................... 1 1.1 Hallmarks of Parkinson’s Disease .................................................................................. 1 1.2 Dopamine Synthesis and Neurotransmission .............................................................. 2 1.3 Nigrostriatal Pathway Responsible for Locomotion ................................................... 2 1.4 Loss of Striatal Dopaminergic Innervation Leads to Parkinson’s Disease ............... 4 1.5 Treatments for Parkinson’s Disease Symptoms are Limited and Problematic ....... 6 2. Chemical Genetic Mouse Model for Parkinson’s Disease ................................................. 11 2.1 Phenotypic-Screening of Compounds in a Parkinson’s Disease Mouse Model .... 11 2.2 Amphetamine Drug Class ............................................................................................. 17 2.3 Aryl-Substituted (±)-trans-Arylcyclopropylamines Derivatives Alleviate Akinesia in Mouse Model .................................................................................................................... 21 2.4 Monoamine B Inhibition is not Responsible for Mechanism of Action .................. 29 2.6 Hypothesis ....................................................................................................................... 33 3. Syntheses .................................................................................................................................. 34 3.1 Original Synthesis of Arylcyclopropylamine-Derivative, Tranylcypromine ........ 34 vi 3.2 Synthetic Strategies ........................................................................................................ 35 3.3 Preparative-Scale Synthesis .......................................................................................... 35 3.3.1 Alternative Rearrangement Reactions .................................................................... 41 3.3.2 Cross-Coupling Reactions ........................................................................................ 43 3.4 Additional Chemical Probes of Interest ...................................................................... 45 3.4.1 Phenethylamines derivatives ................................................................................... 46 3.4.2 MDMA-Derivates, UWA-121 & UWA-122 ............................................................ 46 3.5 Experimental ................................................................................................................... 48 3.5.1 ACPA derivatives ...................................................................................................... 49 3.5.2 UWA derivatives ....................................................................................................... 64 4.1 Unilateral 6-Hydroxydopamine-Lesion Rat ............................................................... 66 4.2 Design and Validation of Animal Model .................................................................... 67 4.3 Acute-Administration of ACPAs Accessed by Forelimb Adjusted Step Task ...... 72 4.4 Conclusions ..................................................................................................................... 74 4.5 Experimental ................................................................................................................... 76 5. G-Protein Coupled Receptors ................................................................................................ 80 5.1 Survey of the GPCRome ................................................................................................ 81 5.2 G-Protein Coupled Receptor’s Structural Components ............................................ 82 5.3 G-Protein Coupled Receptor Biological Functions .................................................... 83 5.3.1 G-Protein Dependent Signaling .............................................................................. 83 5.3.2 G-Protein Independent Signaling ........................................................................... 86 5.4 G-Protein Coupled Receptor Assays ........................................................................... 88 vii 5.4.1 Affinity ........................................................................................................................ 88 5.4.2 Efficacy ........................................................................................................................ 89 6. Mechanistic Affinity Studies ................................................................................................. 90 6.1 Experimental Design ...................................................................................................... 91 6.2 Library of Compounds Assessed ................................................................................. 92 6.2.1 Dopaminergic Targets .............................................................................................. 93 6.2.2 Serotonergic Targets .................................................................................................. 96 6.2.3. Adrenergic Targets ................................................................................................. 102 6.2.4. Histaminergic Targets ............................................................................................ 105 6.2.5 Non-Monoamine Targets ....................................................................................... 106 6.3 Pharmacophoric Considerations ................................................................................ 109 6.3.1 Additional
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