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Caffeine Analogues and Their Evaluation As Inhibitors of Monoamine Oxidase And Syntheses of 8-(phenoxymethyl)caffeine analogues and their evaluation as inhibitors of monoamine oxidase and as antagonists of the adenosine A2A receptor. Rozanne Harmse B.Pharm Dissertation submitted in partial fulfilment of the requirements for the degree Magister Scientiae, in Pharmaceutical Chemistry at the North-West University, Potchefstroom Campus. Supervisor: Prof. G. Terre’Blanche Co-Supervisor: Dr. A. Petzer 2013 Potchefstroom 1 TABLE OF CONTENTS ABSTRACT ................................................................................................................................................. IV UITTREKSEL ............................................................................................................................................. VII ACKNOWLEDGEMENTS ........................................................................................................................... X CHAPTER 1 ................................................................................................................................................... 1 INTRODUCTION AND OBJECTIVES .......................................................................................................... 1 1.1 INTRODUCTION .......................................................................................................................................... 1 1.2 RATIONALE ............................................................................................................................................... 4 1.3 HYPOTHESIS .............................................................................................................................................. 6 1.4 OBJECTIVES ............................................................................................................................................... 7 CHAPTER 2 ................................................................................................................................................... 8 PARKINSON’S DISEASE, MONOAMINE OXIDASE AND THE ADENOSINE A2A RECEPTOR ......... 8 2.1 PARKINSON’S DISEASE........................................................................................................................... 8 2.1.1 General background ............................................................................................................ 8 2.1.2 Pathophysiology – neurochemical and neuropathological features .................................... 9 2.1.3 Etiology .............................................................................................................................. 12 2.1.3.1 Environmental factors ............................................................................................................................ 12 2.1.3.2 Genetic factors ....................................................................................................................................... 14 2.1.4 Pathogenesis ..................................................................................................................... 14 2.1.4.1 Oxidative stress and mitochondrial dysfunction .................................................................................... 14 2.1.4.2 Protein aggregation and misfolding ....................................................................................................... 16 2.1.5 Clinical features, symptoms and diagnosis ....................................................................... 17 2.1.6 Treatment .......................................................................................................................... 18 2.1.6.1 Levodopa (L-dopa) ................................................................................................................................. 18 2.1.6.2 Dopamine receptor agonists .................................................................................................................. 20 2.1.6.3 Catechol-O-methyltransferase (COMT) inhibitors ................................................................................. 21 2.1.6.4 Selective MAO-B inhibitors .................................................................................................................... 21 2.1.6.5 Muscarinic receptor antagonists............................................................................................................ 22 2.1.7 Neuroprotection ................................................................................................................. 22 2.1.7.1 Dopamine receptor agonists .................................................................................................................. 23 2.1.7.2 Adenosine receptor antagonists ............................................................................................................ 23 2.1.8 Conclusion ......................................................................................................................... 23 2.2 MONOAMINE OXIDASE ....................................................................................................................... 25 2.2.1 Introduction ........................................................................................................................ 25 2.2.2 Classification and Characteristics ..................................................................................... 25 2.2.2.1 Classification .......................................................................................................................................... 25 2.2.2.2 Characteristics ........................................................................................................................................ 26 2.2.3 Localization and tissue distribution ................................................................................... 27 2.2.4 Physiological functions ...................................................................................................... 27 2.2.5 Molecular structure and characteristics of MAO ............................................................... 28 2.2.6 The catalytic cycle of MAO-B ............................................................................................ 31 2.2.7 Parkinson’s disease and MAO inhibitors .......................................................................... 33 2.2.8 Adverse effects of MAO inhibitors ..................................................................................... 34 2.2.9 Pharmacology of MAO-B inhibitors ................................................................................... 36 2.2.9.1 Deprenyl ................................................................................................................................................. 36 2.2.9.2 Rasagiline ............................................................................................................................................... 36 2.2.9.3 Lazabemide ............................................................................................................................................ 37 i 2.2.9.4 Ladostigil ................................................................................................................................................ 37 2.2.10 Conclusion ......................................................................................................................... 38 2.3 THE ADENOSINE A2A RECEPTOR ........................................................................................................... 39 2.3.1 Introduction ........................................................................................................................ 39 2.3.2 Adenosine Receptors ........................................................................................................ 39 2.3.3 Basal ganglia organization and adenosine A2A receptors ................................................. 41 2.3.4 Interactions with other neurotransmitter receptors ............................................................ 43 2.3.4.1 Dopamine D2 receptor ........................................................................................................................... 43 2.3.4.2 Glutamate mGlu5 receptor .................................................................................................................... 44 2.3.4.3 Adenosine A1 receptor ........................................................................................................................... 45 2.3.5 Adenosine antagonists and Parkinson’s disease .............................................................. 45 2.3.6 Classification of Adenosine A2A Antagonists ..................................................................... 46 2.3.6.1 Xanthines ............................................................................................................................................... 46 2.3.6.2 Aminouracil Derivatives ......................................................................................................................... 48 2.3.7 Neuroprotection of A2A antagonists in Parkinson’s disease .............................................. 48 2.3.8 Conclusion ......................................................................................................................... 49 CHAPTER 3:................................................................................................................................................ 50 SYNTHESES OF 8-(PHENOXYMETHYL)CAFFEINE ANALOGUES ..................................................
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