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The Effect of School Closure On Actions of benzophenanthridine alkaloids and various synthetic compounds on the cannabinoid-1 (CB1) receptor pathway of mouse brain with particular reference to the effects on [3H]CP55940 and [3H]SR141716A binding, interference with basal and CP55940-stimulated [35S]GTPγS binding, and modification of WIN55212-2-dependent inhibition of L-glutamate release from synaptosomes by Amey S. Dhopeshwarkar MSc., University of Abertay Dundee, 2007 B.Pharm., University of Pune, 2004 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in the Department of Biological Sciences Faculty of Science Amey S. Dhopeshwarkar 2012 SIMON FRASER UNIVERSITY Summer 2012 All rights reserved. However, in accordance with the Copyright Act of Canada, this work may be reproduced, without authorization, under the conditions for “Fair Dealing.” Therefore, limited reproduction of this work for the purposes of private study, research, criticism, review and news reporting is likely to be in accordance with the law, particularly if cited appropriately. Approval Name: Amey S. Dhopeshwarkar Degree: Doctor of Philosophy (Biological Sciences) Title of Thesis: Actions of benzophenanthridine alkaloids and various synthetic compounds on the cannabinoid-1 (CB1) receptor pathway of mouse brain with particular reference to the effects on [3H]CP55940 and [3H]SR141716A binding, interference with basal and CP55940-stimulated [35S]GTPγS binding, and modification of WIN55212-2-dependent inhibition of L- glutamate release from synaptosomes. Examining Committee: Chair: Dr Julian Christians, Associate Professor Dr Russell A. Nicholson Senior Supervisor Associate Professor Dr Christopher Kennedy Supervisor Professor Dr Francis C.P. Law Supervisor Professor Dr Gordon Rintoul Internal Examiner Associate Professor Department of Biological Sciences, SFU Dr Andrew Gifford External Examiner Scientist, Medical Department Brookhaven National Laboratory Date Defended/Approved: August 15, 2012 ii Partial Copyright Licence iii Ethics Statement The author, whose name appears on the title page of this work, has obtained, for the research described in this work, either: a. human research ethics approval from the Simon Fraser University Office of Research Ethics, or b. advance approval of the animal care protocol from the University Animal Care Committee of Simon Fraser University; or has conducted the research c. as a co-investigator, collaborator or research assistant in a research project approved in advance, or d. as a member of a course approved in advance for minimal risk human research, by the Office of Research Ethics. A copy of the approval letter has been filed at the Theses Office of the University Library at the time of submission of this thesis or project. The original application for approval and letter of approval are filed with the relevant offices. Inquiries may be directed to those authorities. Simon Fraser University Library Burnaby, British Columbia, Canada update Spring 2010 Abstract Benzophenanthridine alkaloids (chelerythrine and sanguinarine) inhibited the binding of 3 3 [ H]CP55940 and [ H]SR141716A to mouse brain membranes (IC50s approx. 1-2 µM). Piperonyl butoxide and (S)-methoprene were more potent inhibitors of [3H]CP55940 3 binding (IC50s: 8.2 µM and 16.4 µM respectively) than of [ H]SR141716A binding (IC50s: 21 µM and 63 µM respectively). Binding experiments demonstrated selectivity towards the brain CB1 versus spleen CB2 receptor. 3 Benzophenanthridines reduced the Kd of [ H]CP55940 binding to brain membranes whereas (S)-methoprene and piperonyl butoxide lowered Bmax. These study compounds reduced the association of [3H]CP55940 and [3H]SR141716A, however benzophenanthridines were consistently more effective. In the presence of a saturating concentration of SR141716A, (S)-methoprene and piperonyl butoxide increased dissociation of [3H]SR141716A above that observed with SR141716A alone. All compounds activated [3H]SR141716A dissociation when assayed alone, but (S)-methoprene was the least effective. In separate studies, phthalate 3 diesters reduced the Bmax of [ H]SR141716A without affecting Kd, and increased [3H]SR141716A dissociation above a saturating concentration of AM251. Benzophenanthridines antagonized CP55940-stimulated and basal binding of [35S]GTPγS to the G-protein of mouse brain, whereas piperonyl butoxide and (S)- methoprene inhibited CP55940-stimulated [35S]GTPγS binding only. Inhibition of CP55940-stimulated binding of [35S]GTPγS was also demonstrated with phthalates. 4-Aminopyridine- (4-AP-) induced release of L-glutamate from mouse brain synaptosomes was partially inhibited by WIN55212-2. The inhibitory effect of WIN55212-2 was completely neutralized by AM251, (S)-methoprene, piperonyl butoxide and phthalate diesters, whereas in the presence of WIN55212-2, the benzophenanthridines enhanced 4-AP-induced L-glutamate release above that caused by 4-AP alone. iii The [3H]CP55940 and [3H]SR141716A binding data suggest that the study compounds modify radioligand binding allosterically. The [35S]GTPγS binding results suggest that chelerythrine and sanguinarine are inverse agonists of G-protein-coupled CB1 receptors, while piperonyl butoxide, (S)-methoprene and phthalate diesters are neutral lower potency antagonists. Modulation 4-AP-evoked L-glutamate release from synaptosomes by the study compounds with WIN-55212-2 present strongly supports this latter profiling. Although these compounds exhibit lower potencies versus many conventional CB1 receptor inhibitors, further studies are warranted, given their potential to 1) modify CB1 receptor-dependent behavioral/physiological outcomes in the whole animal, and 2) serve as starting structures for synthesis of novel/more potent G-protein-coupled CB1 receptor blocking drugs. Keywords: Benzophenanthridines; (S)-methoprene; piperonyl butoxide; [3H]CP55940; 35 [ S]GTPγS; L-glutamate; synaptosomes;cannabinoid-1 (CB1) receptor iv Dedication To My Beloved Mom and Dad v Acknowledgements I wish to express my deepest gratitude and appreciation to my senior supervisor, Dr Russell A. Nichoson for his guidance, patience and indefatigable support throughout my graduate research career. I remember the days when Dr Nicholson spared his time even on weekends and holidays to discuss my research and his invaluable suggestions and encouragements have always made me feel confident about my research work. Thorough discussion sessions with him about project and related scientific issues and perspectives have enriched my knowledge in this field. Without Dr Nicholson’s support and effort, I would not have completed my PhD research in time. I believe that I was lucky to have such a knowledgeable senior supervisor and I am fortunate to be his last graduate student. I am very much thankful to Dr Chris Kennedy and Dr Francis C.P. Law for serving as my committe members and their valuable time and inputs during my PhD. They have always been supportive during my studies at SFU. I am also thankful to Mr Saurabh Jain and Ms Kathleen M. Bisset for their help and advice during my research. Finally, I would like to thank my family for their love, support encouragement and always believing in me. vi Table of Contents Approval .......................................................................................................................... ii Abstract .......................................................................................................................... iii Dedication ....................................................................................................................... v Acknowledgements ........................................................................................................ vi Table of Contents .......................................................................................................... vii List of Tables ................................................................................................................. xii List of Figures................................................................................................................xiv Glossary ........................................................................................................................xxi 1. Introduction .......................................................................................................... 1 1.1. Historical significance of cannabis use and cannabinoids ....................................... 1 1.1.1. The early Chinese/Indian era ...................................................................... 1 1.1.2. The period encompassing the early Christian era through to the 18th century ........................................................................................................ 2 1.1.3. The Western medicine era of the 19th and 20th centuries ............................. 2 1.2. Cannabinoids ......................................................................................................... 5 1.2.1. G protein-coupled receptors (GPCRs) and their activation cycle ................. 7 1.2.2. The [35S]GTPγS binding assay .................................................................... 8 1.3. Other cannabinoid receptors .................................................................................. 8 1.4. Cannabinoid-1 Receptors (CB1-Rs) ........................................................................ 9 1.4.1. The structure and activation of CB1-Rs ......................................................
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