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Bradykinin Ligands and Receptors Involved in Neuropathic Pain

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Bradykinin Ligands and Receptors Involved in Neuropathic Pain Bradykinin Ligands and Receptors Involved in Neuropathic Pain Item Type text; Electronic Dissertation Authors Hall, Sara M. Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 26/09/2021 05:03:50 Link to Item http://hdl.handle.net/10150/578606 BRADYKININ LIGANDS AND RECEPTORS INVOLVED IN NEUROPATHIC PAIN by Sara M. Hall ___________________ A Dissertation Submitted to the Faculty of the DEPARTMENT OF CHEMISTRY AND BIOCHEMISTRY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY WITH A MAJOR IN BIOCHEMISTRY In the Graduate College THE UNIVERSITY OF ARIZONA 2015 1 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Sara M. Hall titled Bradykinin Ligands and Receptors Involved in Neuropathic Pain and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy ____________________________________________________________Date: 8/5/15 Prof. Victor J. Hruby ____________________________________________________________Date: 8/5/15 Prof. Josephine Lai ____________________________________________________________Date: 8/5/15 Prof. Nancy Horton ____________________________________________________________Date: 8/5/15 Prof. John Jewett Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. ____________________________________________________________Date: 8/5/15 Dissertation Director: Prof. Victor J. Hruby 2 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED: __Sara M. Hall____ 3 ACKNOWLEDGMENTS First and foremost I would like to express my sincere gratitude to my advisor, Dr. Victor J. Hruby for his immense amount of support the past years. I greatly admire his knowledge, work ethic and guidance. I'm very appreciative of not only the chemistry knowledge he taught me, but also the life lessons. I also owe a great amount of gratitude to Dr. Josephine Lai, who spent 100s of hours teaching me pharmacology. She also was instrumental in teaching me how to analyze and interpret the data. Thanks for all the years of patience, sharing your knowledge (in science and life), and support. Thanks to David Rankin for teaching me pharmacology techinques. Gratitude also goes to Dr. Frank Porreca and Dr. Todd Vanderah for allowing me to do many of the biological assays in their labaratories and the support of their members. Thanks to my committee members, Dr. Vahe Bandarian, Dr. Nancy Horton, and Dr. John Jewett for all their valuable comments and suggestions. I also like to thank all the Hruby group members but especially Dr. Yeon Sun Lee for being a chemistry genius and being a great editor. Also, Dr. Scott Cowell for his advice the past years. Thank you to Lindsay LeBaron, an undergraduate under my supervision, for all her hard work the past years. I give many thanks to some fellow graduate students; Dr. Christine Kaiser, Dr. Bethany Remeniuk, and Cyf Nadine Ramos-Colon for the many laughs and stories that have made graduate school bearable. Lastly, I thank my boyfriend for putting up with me and the stress of graduate school. 4 Dedicated to my loving parents, Raymond and Charlotte Hall, grandparents Jerry and Sandra Bolt and brothers Brian and Joe Hall Even with many miles in between they gave unending love and support 5 TABLE OF CONTENTS LIST OF TABLES.............................................................................................................13 LIST OF FIGURES...........................................................................................................15 ABSTRACT.......................................................................................................................20 ABRREVIATIONS...........................................................................................................22 INTRODUCTION.............................................................................................................25 Chronic pain...................................................................................................................25 Therapeutics for neuropathic pain.................................................................................26 Dyn A, an extraordinary opioid peptide........................................................................28 Dyn A, an endogenous ligand for the kappa opioid receptor (KOR)............................29 Structure activity relationship (SAR) of Dyn A at the KOR.........................................30 KOR antagonists for the treatment of pain....................................................................33 Future directions for Dyn A based KOR ligands...........................................................35 Non-opioid effects of Dyn A.........................................................................................35 N-methyl D-aspartate receptor (NMDAR) as the target for non-opioid effects............37 Bradykinin receptors (BRs) as the target for non-opioid effects...................................38 GPCRs as a target for drug design.................................................................................41 Signaling of GPCRs.......................................................................................................43 Aims...............................................................................................................................44 PART I: DESIGN AND SYNTHESIS OF DYNORPHIN A ANALOGUES INTERACTING AT THE BRADYKININ 2 RECEPTOR WITH EVALUATION OF BINDING, STABILITY, AND TOXICITY.....................................................................45 INTRODUCTION.........................................................................................................46 6 TABLE OF CONTENTS-Continued Model of BK bound to the B2R.................................................................................46 Strategies in designing analogues..............................................................................47 Peptides as therapeutics.............................................................................................48 Rational......................................................................................................................50 CHAPTER I: MATERIALS AND METHODS............................................................51 1.1 Reagents for Fmoc Solid Phase Peptide Synthesis (SPPS)................................51 1.2 SPPS.....................................................................................................................51 1.3 Peptide purification and analysis.........................................................................53 1.4 Materials for membrane preparations and competition assays............................53 1.5 Membranes preparations for; rat brain, hB2R-HEK, and hB1R-HEK cells........................................................................................................................54 1.6 Protein determination...........................................................................................54 1.7 Competitive radioligand binding assay................................................................54 1.8 Rat and human plasma stability assays................................................................55 1.8.1 Isolation and validation of a degraded fragment of LYS1044.....................55 1.8.2 Data analysis.................................................................................................55 1.9 Cell culture...........................................................................................................56 1.10 XTT cytotoxicity assay......................................................................................56 CHAPTER II: RESULTS..............................................................................................57 2.1 Establishment of Dyn A-(2-13) binding to the B2R............................................57 2.1.1 [3H] DALKD binding...................................................................................57 2.1.2 High affinity of Dyn A-(2-13) at the B2R....................................................58 7 TABLE OF CONTENTS-Continued 2.1.3 Selectivity of Dyn A-(2-13) for the B2R over the B1R................................60
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