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Thesis Submitted for the Degree of Doctor of Philosophy University of Bath Department of Pharmacy and Pharmacology May 2006 University of Bath PHD Investigation of aminotetralins as novel opioid receptor antagonists Williams, Ian Andrew Award date: 2006 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 10. Oct. 2021 INVESTIGATION OF AMINOTETRALINS AS NOVEL OPIOID RECEPTOR ANTAGONISTS Ian Andrew Williams A thesis submitted for the degree of Doctor of Philosophy University of Bath Department of Pharmacy and Pharmacology May 2006 V , • A “• * .-1. COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the prior written consent of the author. This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purposes of consultation. UMI Number: U490001 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 U490001 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 UNIVERSITY OF BATH LIBRARY tf-o ~ h MAY 2007 i PkV. ABSTRACT There has been much evidence in recent years to suggest that the k opioid receptor plays a significant role in mediating a number of behavioural disorders including drug abuse and depression. Previous in vitro evaluation in the group of secondary and tertiary amines derived from 2-amino-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-7-ol showed that all behaved as pure opioid antagonists. These findings prompted further synthetic and pharmacological investigations of this scaffold, with the eventual aim of developing a short- acting selective opioid antagonist to further probe the k receptor. Using molecular modelling, a series of ligands were designed based on a previously prepared Af-cinnamyl analogue but incorporating a second basic nitrogen intended to mimic the N17’ nitrogen of norBNI and increase k selectivity. Synthesis and pharmacological evaluation of the key intermediates revealed that the ortho- NH2 derivative possessed the greatest k affinity and antagonist potency, although the corresponding NO 2 analogue also exhibited high k antagonist potency in the functional assay. Many of the synthetic steps were optimised and an improved protocol for the preparation of 7-methoxytetralone was developed. Based on findings that aminotetralins possessing certain two-atom chains at the 3- position display high opioid receptor affinity, a second series of //-substituted ligands utilising an aminotetralin scaffold bearing a 3 -OCH3 group were synthesised which included an improved method for the hydride reduction of an oxime to aziridine. Preliminary pharmacological results indicate a considerable gain in opioid receptor binding whilst retaining pure antagonist activity; a novel selective k antagonist ligand was also identified. The encouraging results of the 3-OCH3 analogues prompted investigation of a third series of ligands bearing 3-amino substituents, in order to evaluate the effect of an additional basic group in the scaffold. A synthetic route was devised which made use of a ‘nosyl’ group to activate the aziridine and introduce the desired ‘address’ side-chain. The 3- pyrrolidino analogue was successfully prepared by this method and it is anticipated that the route is flexible enough to allow a diverse range of analogues to be prepared in due course. Finally, the preparation of a novel alkene intermediate utilising a cyclisation strategy was briefly investigated with the aim of identifying a synthetic route to future series of ligands which is efficient, economical and environmentally friendly. ACKNOWLEDGEMENTS I am indebted to a great many people for enabling me to retain my general sanity during the past three years or so in Bath. First and foremost I would like to thank my supervisor, Dr. Steve Husbands, for his good humour, enduring patience and always being available for advice and reassurance on all matters chemical or otherwise. Thanks must also go to Dr. John Lewis for his professional input and guiding the project in the right direction. In terms of lab support, I am most indebted to Dave Rennison for teaching me almost everything I know about practical chemistry and providing a great deal of entertainment both inside and outside of the laboratory (which fortunately made up for his shocking taste in music!). Thanks must also go to Claire Goodyer for corrupting me into taking regular tea breaks, without which I would never have kept up to date with all the departmental gossip; Cedric for his amazing singing ability and nights at the cinema; Adrian for our music discussions and love of ‘tinpot’ local radio and Shefali for passing the reins of the aminotetralin project onto me in my first term at Bath. For those rare moments away from the lab, my thanks go to Becky Hurwitz of PCCAL for three years of friendship, those discussions on the meaning of life at the pub and for her alternative and entertaining approach to everything (plus her attempts at explaining postmodernism which I still don’t understand!). Thanks also to my previous housemates at Park Avenue (Jude, Emily, Steve and Xun), everyone in lab 3.5 (especially Joey and Anna) for the laughs over the years and Tom Moles (for our conversations on cosmology) and all the other pharmacy people I met along the way. Finally, I would like to thank my family for their support, both personal and financial and for always providing free accomodation and catering whenever needed! I also gratefully acknowledge the National Institute on Drug Abuse (NIDA) for funding this project. TABLE OF CONTENTS CHAPTER 1 INTRODUCTION 1.1 History of opioid research ........................................................................................ 1 1.2 Opioid receptors.......................................................................................................2 1.2.1 The discovery o f opioid receptors .............................................................................2 1.2.2 Opioid receptor types.................................................................................................2 1.2.3 The structure of opioid receptors..............................................................................3 1.2.4 Distribution and pharmacological profiles of p, S and k opioid receptors 3 1.3 The use of opioids in medicine and society ............................................................. 4 1.3.1 The mechanism o f opioid analgesia .........................................................................4 1.3.2 Other medicinal uses of opioids ................................................................................5 1.3.3 Opioid tolerance and dependence .............................................................................7 1.3.4 The mechanism of tolerance and physical dependence ........................................ 8 1.4 The development of selective opioid antagonists ...................................................9 1.4.1 The message-address concept and the development of naltrindole ...................10 1.4.2 NorBNI and GNTI: Highly potent and selective kappa opioid antagonists.... 11 1.5 Kappa antagonists: A target for the treatment of addiction and depression. 12 1.5.1 The mechanism of psychological dependence and the role of dynorphin 12 1.5.2 Limitations o f current k opioid antagonists ......................................................... 14 1.6 Literature survey of “small molecule” opioid receptor antagonists .................16 1.7 Aminotetralins: Novel ‘message’ scaffolds for the development of selective opioid receptor antagonists ...................................................................................... 18 1.8 Investigation of 2-amino-l,l-dimethyl-l,2,3,4-tetrahydronaphthalen-7-ol as a new opioid receptor ‘message’.................................................................................23 1.9 Research aims .........................................................................................................
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