................................................................................................................................. iv ACKNOWLEDGEMENTS...............................................................................vi TABLE OF CONTENTS...................................................................................ix LIST OF SYMBOLS AND ABBREVIATIONS......................................................xii LIST OF FIGURES .................................................................................................................. xvii LIST OF TABLES ..................................................................................................................... xxi LIST OF SCHEMES ................................................................................................................ xxii CHAPTER I: INTRODUCTION 1.1 Aporphine Alkaloids 1.1.1 Background and Occurrence.........................................................2 1.1.2 Biosynthesis of Aporphine Alkaloids...............................................2 1.1.3 Common Synthetic Approaches to Aporphine Alkaloids........................5 1.1.4 Pharmacological Effects of Aporphine Alkaloids..................................8 1.2 5-HT2A Antagonists 1.2.1 Background...........................................................................14 1.2.2 Clinical Significance of 5-HT2A Antagonists...............................................14 1.2.3 Structural Classifications of 5-HT2A Antagonists................................18 1.2.4 5-HT2A Antagonist Pharmacophore................................................20 1.2.5 Recent Review of 5-HT2A Antagonists............................................23 1.3 Conclusions......................................................................................30 CHAPTER II: SYNTHESIS AND EVALUATION OF NANTENINE ANALOGUES 2.1 Background......................................................................................33 2.2 Nantenine As a Lead For The Identification of New 5-HT2A Antagonists..............33 2.2.1 Previous Structure Activity Relationship (SAR) Studies.......................34 2.2.2 Summary of Previous Findings....................................................36 2.3 Rationale & Central Hypothesis...............................................................37 x 2.4 Results 2.4.1 C4 Phenyl Analogues...............................................................38 2.4.2 Isochroman Analogues...............................................................48 2.4.3 Ring D Indole-Aporphine Analogues...............................................60 2.4.4 C3 Analogues........................................................................69 2.5 Conclusions......................................................................................74 2.6 Experimental 2.6.1 Chemistry.............................................................................76 2.6.2 Biological Evaluations............................................................137 CHAPTER III: SYNTHESIS & EVALUATION OF TRIS-(PHENYLALKYL) AMINES 3.