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The Search for Analgesic Compounds from Higher Plants

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THE SEARCH FOR ANALGESIC COMPOUNDS FROM HIGHER PLANTS Thesis presented by JULIA H. SAMPSON (B.Sc.) for the degree of Doctor of Philosophy Department of Pharmacognosy The School of Pharmacy University of London 1995 ProQuest Number: 10104867 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10104867 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 TABLE OF CONTENTS PAGE NUMBER Acknowledgements 1 Abstract 2 List of Abbreviations 5 List of Figures 6 List of Tables 9 CHAPTER ONE ; INTRODUCTION 1.1 Introduction 11 1.2 Uses of Plants 12 1.3 Initial Separation of Phytochemicals 13 1.4 Medicinal Plants for Use as Potential Analgesic Drugs 16 1.5 Alternative Health Care 19 1.5.1 Plants in Alternative Systems of Medicine 19 1.5.2 African Medicine 20 1.5.3 Ayurvedic Medicine 20 1.5.4 Traditional Chinese Medicine 21 1.6 Documenting and Evaluating Herbal Remedies 21 1.6.1 Intraspecific Variation 21 1.7 Secondary Metabolites Derived from Plant Metabolism 21 1.7.1 Alkaloids 28 1.7.2 Phenolics 31 1.7.3 Terpenoids 35 1.8 Nociception in the Mammalian Central Nervous System 37 1.9 The First Opioid Agonists and Antagonists 38 1.10 Non Opioid Analgesic Drugs 38 1.11 Mediation of Pain in the Mammalian CNS 40 1.12 Inflammation and Nociception 41 1.13 Discovery of Bradykinin and its Physiological Effects 43 1.14 Kininogens, Kallikreins and Kinins 45 1.15 The Mechanisms of Bradykinin Sensory Neurone Excitation 45 and Sensitisation 1.16 Bradykinin Receptors 48 1.17 Characterisation of Bradykinin Receptors 50 1.18 The Rationale for New Bradykinin Antagonists 52 1.19 Signal Transduction Mechanisms of Bradykinin Via 53 BK H Receptor Subtypes 1.20 Seven Transmembrane Receptors 54 1.21 The Structure of G-Protein Coupled Receptors 55 1.22 Signalling by Seven Transmembrane Receptors 56 1.23 Regulation of Bradykinin Activity 57 1.24 CGRP and Mediation of Nociception in the Mammalian CNS 59 1.25 CGRP Immunoreactivity 59 1.26 Physiological Effects Mediated by CGRP 60 1.27 CNS Actions of CGRP 61 1.28 The Rationale for the Use of a CGRP Antagonist in Migraine 62 CHAPTER ONE : INTRODUCTION TABLE OF CONTENTS PAGE NUMBER 1.29 Co-localisation of CGRP with Other Neuropeptides 63 1.30 CGRP and Calcitonin Receptors 64 1.31 CGRP Receptor Agonists and Antagonists 65 1.31.1 CGRP 8-37 65 1.31.2 [Tyr]CGRP28-37 66 1.31.3 Human Calcitonin 66 1.32 CGRP Receptors Expressed in the SK-N-MC Cell line 66 1.33 Cleavage of CGRP 66 1.34 Substance P and the Neurokinin 1 Receptor 67 1.35 Aims 68 CHAPTER TWO: MATERIALS AND METHODS PAGE NUMBER 2.1 Considerations for Binding Assays 72 2.2 The Initial Development of the Bradykinin Radioligand 73 Binding Assay using a Rat Uterus Membrane Preparation 2.3 Cloning of the BK H Receptor in Chinese Hamster 74 Ovary Cells 2.4 Expression of the BK H Receptor in Chinese 75 Hamster Ovary Cells 2.5 Assay Conditions for the BK H Screen 77 2.5.1 Radiochemicals 77 2.5.2 Stock Radioligands 77 2.5.3 Non-Radioactive Ligands 78 2.5.4 Determination of Non Specific Binding 78 2.6 Separation of Bound from Free Ligand 77 2.7 Measurement of Radioactivity for Bradykinin 78 2.8 Data Analysis and Capture 78 2.9 The Preparation and Use of CGRP Membranes 79 2.10 Assay Conditions for the CGRP Screen 79 2.10.1 Non-Radioactive Ligands 79 2.10.2 Measurement of Radioactivity and Data Analysis 79 2.11 Determination of the Protein Content for BK H and CGRP 80 2.12 Time Course Studies for the BK H and CGRP Assays 81 2.12.1 Calcitonin G^ne Related Peptide 81 2.13 Saturation Analysis of the BK H and CGRP Receptors 83 2.13.1 Scatchard Analysis 83 2.14 Association and Dissociation Studies 83 2.15 Characterisation of the BK H Receptor 83 2.16 The Neurokinin 1 Receptor Radioligand Binding Assay 84 2.17 Composition of Solutions 86 2.18 Assay Protocols for Bradykinin BK H and CGRP 87 2.19 Assay Protocol for the CGRP Binding Assay 87 CHAPTER TWO ; MATERIALS AND METHODS_________ PAGE NUMBER 2.20 Assay Protocol for the BK H Binding Assay Using Rat Uterus 88 Membranes 2.21 Thin Layer Chromatography for Detection of Terpenoids 88 2.22 Preparation of Plant Extracts for Screening in in vitro 89 Binding Assays 2.23 Extraction and Isolation of Bioactive Entities 91 2.24 Plant Sample Preparation for Extraction and Isolation 91 2.25 Sample Processing on LH20 Columns 91 2.26 Automated Multiple Development-High Pressure Liquid 92 Thin Layer Chromatography 2.27 Preparation of Plant Extracts for in vivo Tests 92 2.28 Preparation of Mice for the in vivo Screening of Plant Extracts 94 in the Acetic Acid Writhing Test. CHAPTER THREE : RESULTS__________________________ PAGE NUMBER 3.1 The Results of Screening Methanol Plant Extracts in the in vitro 95 Bradykinin BK H Rat Uterus Membrane Preparation 3.2 Results of the Development Experiments for the Bradykinin 96 BK H Assay. 3.3 Time Course Studies for the Bradykinin BK H Assay 96 3.4 Dissociation Studies of the Bradykinin BK H Receptor 96 3.5 Scatchard Analysis of the Bradykinin BK H Receptor 103 3.6 Displacement Curves of Bradykinin Analogues in the Bradykinin 109 BK H Assay. 3.7 Results from the CGRP Radioligand Binding Assay : Time Course Studies 112 3.8 Scatchard Analysis of the CGRP Receptor 114 3.9 Displacement Curve of CGRP in the CGRP Assay 116 3.10 Results of Screening 300 Ethnomedically Selected and 335 140 Non-Selected Plant Extracts in the Bradykinin BK H Assay 3.11 The In vitro and In vivo Results of the Methanol Extracts of Panax 143 ginseng and Ipomea pes-caprae 3.11.1 The in vivo Results of Panax ginseng and Ipomea pes-caprae 153 3.13 The Extraction of Bioactive Entities from Symplocos leptophylla 154 3.14 The Procedure Followed for the Extraction of Bioactive Entities 155 from Symplocos leptophylla 3.14.1 Results of Symplocos leptophylla using AMD 158 3.15 Displacement Curves of Fractions 1-8 from Symplocos leptophylla 174 in the Bradykinin BK H Assay CHAPTER FOUR ; DISCUSSION_________________________ PAGE NUMBER 4.1 A Discussion of Methods Available for Selecting Plants 176 for Analgesic Bioactivity 4.2 Discussion of Results from Screening Non-Selected and 181 Ethnomedically Selected Plants for Novel Leads to Analgesics 4.3 Non Peptide Bradykinin Antagonists 182 4.4 The Partial Purification of Symplocos leptophylla 188 4.5 Non Selective Analgesic Effects of Plants Used in Traditional 190 Medicine : Discussion of In vivo Results 4.6 Considerations of the Difficulties Encountered in Bioassay Guided 194 Fractionation of Plant Extracts 4.7 Final Conclusions 195 4.8 Future Work 196 APPENDIXES 217 REFERENCES 234 ACKNOWLEDGEMENTS I very gratefully acknowledge and thank my supervisor Professor J.David Phillipson for his help, guidance and friendship throughout the three years spent studying for this Ph.D., which has contributed to my interest and enthusiasm for this work. I am also indebted to him for his help in editing this thesis. My sincere thanks are also expressed to Professor Norman G.Bowery for his help and support whilst studying in the department of Pharmacology at the University of London, and for his help in editing this thesis. I am indebted to Dr. M.J.O’Neill, Dr. RM.Tait and Dr. J.G.Houston at Glaxo Group Research for their support and unlimited use of facilities during this research. My thanks also to Dr .J.A. Lewis in the division of New Lead Discovery for the supply of plant samples and to Mr. J.G. Farthing for his help and supervision whilst carrying out the chromatographic techniques. My thanks are also expressed to Mr. S. Fogarty in the department of Biomolecular Screening at Glaxo Group Research for help with the radio - ligand binding techniques used in this project, to Ms. T. Shaw-Hamilton for screening plant extracts in the Neurokinin 1 assay, to Mr. J.Coote for the preparation of CGRP membranes and to Dr. G.Vassart at the University of Belgium for the Chinese Hamster Ovary cells which express the bradykinin BK II receptor. I am also grateful to Ms. Marzia Malkangio from the department of Pharmacology, University of London for her help with the in vivo animal studies, and to Dr. Ian Bates in the department of Pharmacy Practice at the University of London for his kind help with the statistical analyses used for the in vivo research. I am very grateful to Ms. P. J.Harrington for the preparation of the results tables. Thanks are given to my parents for their encouragement and support, and I am indebted to my partner Shaun for his patience, help and encouragement throughout these three years. I would like to thank the BBSRC (formerly SERC) for the provision of a grant enabling me to study for this Ph D and to Glaxo Research and Development for their sponsorship.
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