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Isolation and Chemical and Pharmacological Characterization of Potential Trace Amine-Associated Receptor Antagonist from Plant Sources Isolation and Chemical and Pharmacological Characterization of Potential Trace Amine-Associated Receptor Antagonist from Plant Sources A thesis submitted in accordance with the conditions governing candidates for the degree of DOCTOR OF PHILOSOPHY Presented by Gaudencio M. Natividad Division of Pharmacology Welsh School of Pharmacy Cardiff University, Cardiff, UK 2010 UMI Number: U584493 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. Dissertation Publishing UMI U584493 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 DECLARATION This work has not previously been accepted in substance for any degree and is not concurrently submitted in candidature for any degree (candidate) STATEMENT 1 This thesis is being submitted in partial fulfilment of the requirements for the degree of PhD (candidate) STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. (candidate) STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and inter-library loan, and for the title and summary to be made available to outside organizations. (candidate) AKNOWLEDGEMENTS I would like to express my gratitude to Prof. Kenneth Broadley for his expert supervision, advice, encouragement and guidance during this project. I would also like to thank Dr. Emma Kidd and Dr. William Ford for their scientific expertise and valuable discussions that helped the completion of this thesis. I would also like to extend my appreciation to Dr. Claire Simons for her expertise and help in the plant extraction, isolation and structure elucidation. I also extend my thanks to the technical staff and post graduate students for their support and friendship during the duration of this study. I would also like to extend my gratitude to the Ford Foundation - International Fellowship Program for supporting this research especially to Ms. Luisa Feman and Ms. Criselda Doble. I would like also to thank Liezel and Jabeth for their help and friendship during my stay here in Cardiff. I would like to thank my wife, Annabelle, for her kind love and understanding. I would also like to express my appreciation for her help in the cultivation and collection of my plant samples. Finally, and by no means least, I would like to thank my kids, Kiarra, Karlos and Kristin for their love and support. ABSTRACT The present study describes the preliminary evaluation of Philippine medicinal plants Artemisia vulgaris, Chrysanthemum coronarium, Moringa oleifera, Sesbania grandiflora and Vitex negundo for their antagonistic activity at selected biogenic amine receptors on smooth muscle of the airways, gastrointestinal tract and vascular system. The antagonistic activity of these plants were studied against dose-response curves for contractions of the guinea pig ileum, trachea and aorta to 5-hydroxytryptamine (5-HT 2 receptors), methacholine (M3 muscarinic receptors), histamine (Hj receptors), phenylephrine (di-adrenoceptors) and P-phenylethylamine (trace amine-associated receptors, TAARj). The methanolic extracts of S. grandiflora (flowers and leaves) revealed the presence of histamine Hi receptor and muscarinic M 3 receptor antagonist in the ileum. The A. vulgaris chloroform (AV-CHC13) and methanol (AV-MeOH) extracts, and the acid-base extract of V negundo (VN-E) showed histamine Hi antagonism in the ileum and trachea. Further analysis of AV-CHC13 isolated two major components yomogin and 1,2,3,4-diepoxy-l l(13)-eudesmen- 12,8-olide. Yomogin a sesquiterpene lactone exhibited a novel histamine Hi receptor antagonism in the ileum. Repeated exposure of aortic rings to phenylephrine and [5-PEA CRCs produced significant increases in maximum vascular tension due to enhanced intracellular Ca2+ mobilization. Both the AV-CHC1 3 and VN-E inhibited this enhanced response. Further analysis of AV-CHC1 3 revealed that it is probably inhibiting the increase of vascular tone mediated via intracellular Ca2+ release regulated by ryanodine. This study further validates the traditional use of S. grandiflora, A. vulgaris and V negundo in the treatment of hyperactive gut, asthma and hypertension. Table of Contents Isolation and Chemical and Pharmacological Characterization of Potential Trace Amine-Associated Receptor Antagonist from Plant Sources Chapter 1: General introduction 1.1 Introduction ...................................................................................... 2 1.2 Biogenic amines ............................................................................... 3 1.3 Acetylcholine................................................................................... 14 1.4 G protein-coupled receptors ............................................................. 16 1.5 Natural products ............................................................................... 30 1.6 Philippine medicinal plants .............................................................. 34 1.7 Aims of the thesis............................................................................. 47 Chapter 2: Pharmacological methods: control responses to standard agonist on guinea-pig ileum, trachea and aorta 2.1 Introduction ...................................................................................... 51 2.2 Aim s.................................................................................................. 53 2.3 Methods and Material ....................................................................... 54 2.4 Results.............................................................................................. 63 2.5 Discussion ........................................................................................ 96 Chapter 3: Pharmacological effects of Sesbania grandiflora and Chrysanthemum coronarium extracts on responses of the guinea pig ileum to 5-HT, methacholine, histamine and 0-PEA 3.1 Introduction ....................................................................................... 106 3.2 Aims.................................................................................................. 107 3.3 Materials and Methods ..................................................................... 108 3.4 Results............................................................................................... I ll 3.5 Discussion ......................................................................................... 130 3.6 Conclusion ......................................................................................... 133 Chapter 4: Pharmacological effects of Vitex negundo and Moringa oleifera acid-base extracts on responses of pig ileum, trachea and aorta to 5- HT, methacholine, histamine, phenylephrine and 0-PEA 4.1 Introduction ....................................................................................... 135 4.2 Aims.................................................................................................. 136 4.3 Materials and Methods ...................................................................... 137 4.4 Results............................................................................................... 140 4.5 Discussion ......................................................................................... 160 4.6 Conclusion ......................................................................................... 165 Chapter 5: Pharmacological effects of Artemisia vulgaris on responses of the guinea pig ileum to 5-HT, methacholine, histamine and 0-PEA, and trachea to histamine and 0-PEA 5.1 Introduction ....................................................................................... 167 5.2 Aims.................................................................................................. 168 5.3 Materials and Methods ...................................................................... 169 5.4 Results............................................................................................... 173 5.5 Discussion ......................................................................................... 204 5.6 Conclusion ......................................................................................... 208 vi Chapter 6: Pharmacological effects of Artemisia vulgaris on responses of the guinea pig aorta to phenylephrine and p-PEA 6.1 Introduction ....................................................................................... 210 6.2 Aim s.................................................................................................. 211 6.3 Materials and Methods ...................................................................... 212 6.4 Results................................................................................................ 215 6.5 Discussion.......................................................................................... 231 6 . 6 Conclusion ......................................................................................... 237 Chapter 7: General Discussion 7.1 General
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