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Pharmacological Characterization of Novel Opioid Receptor Ligands Aimed at Reducing the Development of Tolerance

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Pharmacological Characterization of Novel Opioid Receptor Ligands Aimed at Reducing the Development of Tolerance Graduate Theses, Dissertations, and Problem Reports 2014 Pharmacological Characterization of Novel Opioid Receptor Ligands Aimed at Reducing the Development of Tolerance Jason Randall Healy West Virginia University Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Healy, Jason Randall, "Pharmacological Characterization of Novel Opioid Receptor Ligands Aimed at Reducing the Development of Tolerance" (2014). Graduate Theses, Dissertations, and Problem Reports. 616. https://researchrepository.wvu.edu/etd/616 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. Pharmacological Characterization of Novel Opioid Receptor Ligands Aimed at Reducing the Development of Tolerance Jason Randall Healy A dissertation submitted to the School of Pharmacy at West Virginia University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmaceutical and Pharmacological Sciences Rae R. Matsumoto, Ph.D., Chair Andrew Coop, Ph.D. Jason D. Huber, Ph.D. Stephen G. Graber, Ph.D. Charles D. Ponte, Pharm.D. Department of Basic Pharmaceutical Sciences Morgantown, West Virginia 2013 Keywords: Antinociception, conformationally sampled pharmacophore, delta antagonist, mu agonist, opioid receptor, tolerance Copyright 2013 Jason Randall Healy ABSTRACT Pharmacological Characterization of Novel Opioid Receptor Ligands Aimed at Reducing the Development of Tolerance Jason Randall Healy The three opioid receptor subtypes, mu (µ), delta (δ) and kappa ( κ) have long been associated with analgesia. Traditional opioid analgesics exert their effects through µ receptors located in the CNS. Recent studies suggest that the development of opioid analgesics displaying dual properties of µ agonism and δ antagonism could be of benefit by retaining potent analgesic properties while reducing the development of tolerance with chronic administration. UMB 425 displays high affinity at the µ receptor (K i = 3.2 ± 0.14 nM), moderate affinity at the δ and κ receptor In vitro [35 S]GTP γS functional assay results indicate that UMB 425 acts as partial agonist at the µ receptor, whilst having competitive antagonistic properties at the δ receptor. UMB 425 displays potent acute analgesic activity in vivo for both the hot plate and tail-flick assays, comparable to morphine itself. To ensure proper opioid-induced mechanisms pretreatment studies were performed using naloxone, a non-selective opioid antagonist, and nor-BNI, a selective κ-antagonist. Naloxone attenuates the analgesic effects induced by an acute ED 90 of UMB 425, while nor-BNI shows no significant reduction. A chronic dosing paradigm was designed to determine UMB 425 induced analgesic tolerance. UMB 425 maintains significantly higher levels of analgesia compared to morphine on the fifth day of this chronic dosing paradigm. A dose-response challenge performed on the sixth day of this paradigm indicates a smaller shift in respective ED50 values for UMB 425 as compared to morphine for both the tail-flick (1.3-/6.4-fold) and hot plate (3.0-/7.8-fold) assays, effectively demonstrating reduced analgesic tolerance liabilities for UMB 425. Dedicated to My loving mother Shirl Lamaster Healy The loving memory of my late father Randall Lawrence Healy The continuous support from my best friend Elizabeth Rose Earley 3 ACKNOWLEDGMENTS My upmost gratitude to my mentor Dr. Rae R. Matsumoto. She provided me with ample opportunities for success. I am grateful for her support and guidance while at West Virginia University. I would also like to acknowledge my committee members, Dr. Andy Coop, Dr. Jason D. Huber, Dr. Stephen G. Graber, and Dr. Charles D. Ponte, for their guidance and insight. Special thanks to the laboratory of Dr. Andrew Coop and Dr. Alexander MacKerell at the University Of Maryland School Of Pharmacy for the synthesis and molecular modeling of compounds for my studies. I would also like to acknowledge the support I received from the members of the Matsumoto laboratory during my tenure. 4 TABLE OF CONTENTS ABSTRACT ................................................................................................................................. 2 DEDICATION .............................................................................................................................. 3 ACKNOWLEDGEMENTS ........................................................................................................... 4 TABLE OF CONTENTS .............................................................................................................. 5 FIGURES AND TABLES ............................................................................................................. 7 ABBREVIATIONS ....................................................................................................................... 9 CHAPTER 1. Background and Objectives ................................................................................ 11 1.1. Pain Management ............................................................................................................. 12 1.2. Opioid Narcotics ................................................................................................................ 14 1.3. Opioid Receptors .............................................................................................................. 17 1.4. Opioid Mechanism of Action ............................................................................................... 20 1.5. Opioid Induced Tolerance ................................................................................................. 22 1.6. Mu/Delta Opioid Receptor Interactions .............................................................................. 24 1.7. Objectives ......................................................................................................................... 26 1.8. Contributions ..................................................................................................................... 28 CHAPTER 2. Structural Optimization of Mixed Mu Agonist/Delta Antagonist Ligands ............... 29 2.1. Introduction ........................................................................................................................ 30 2.2. Methods ............................................................................................................................. 32 2.3. Results ............................................................................................................................... 41 2.4. Discussion ......................................................................................................................... 48 2.5. Contributions ...................................................................................................................... 50 CHAPTER 3. Antinociceptive Activity of Novel UMB Opioid Ligands In Vivo ............................. 51 3.1. Introduction ........................................................................................................................ 52 3.2. Methods ............................................................................................................................. 53 3.3. Results ............................................................................................................................... 55 3.4. Discussion.......................................................................................................................... 57 3.5. Contributions ...................................................................................................................... 59 CHAPTER 4. Evaluation of Tolerance Liabilities of Novel UMB Opioid Ligands In Vivo ............ 60 4.1. Introduction ........................................................................................................................ 61 4.2. Methods ............................................................................................................................. 62 4.3. Results ............................................................................................................................... 63 4.4. Discussion.......................................................................................................................... 65 4.5. Contributions ...................................................................................................................... 67 5 CHAPTER 5. Conclusions and Future Studies.......................................................................... 68 5.1. Summary ........................................................................................................................... 69 5.2. Future Studies and Direction .............................................................................................. 69 REFERNCES
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