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Allosteric Modulation of the Mu Opioid Receptor ALLOSTERIC MODULATION OF THE MU OPIOID RECEPTOR by Kathryn Elsa Livingston A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Pharmacology) in The University of Michigan 2016 Doctoral Committee: Professor John R. Traynor, Chair Professor Margaret E. Gnegy Associate Professor Georgios Skiniotis Professor John J. G. Tesmer © Kathryn Elsa Livingston 2016 Acknowledgements First, I would like to thank Dr. John Traynor. He has been an immensely supportive mentor who has always taken an interest in my development as a scientist and student. I am grateful for his patience, wisdom, and trust. Secondly, I wish to thank the additional members of my thesis committee: Drs. Margaret Gnegy, Georgios Skiniotis, and John Tesmer who have provided valuable comments and insight into my project. Nest, I would like to thank all of the members of the Traynor laboratory, both past and present, including Aaron Chadderdon, Chao Gao, Abigail Fenton, Nicholas Griggs, James Hallahan, Dr. Todd Hillhouse, Dr. Jennifer Lamberts, Claire Meurice, Dr. Lauren Purington, Evan Schramm, Nicolas Senese, Alex Stanczyk, Omayra Vargas-Morales, Dr. Qin Wang, and Wyatt Wells. They have all made the lab a wonderful, vibrant environment. I would also like to thank the various colleagues and collaborators for their contributions to this thesis. From the University of Michigan, I would like to thank Dr. Emily Jutkiewicz and her laboratory for helpful discussions and suggestions, Drs. Yoichi Osawa and Jorge Iñiguez- Lluhi for use of laboratory equipment, the Center for Chemical Genomics and the staff for help using the OctetRed®, and Jacob Mahoney for purification of proteins and help in establishing the interformetry technique in the rHDL system for use in Chapter 5. I would like express gratitude to Drs. Andrew Alt and Neil Burford from Bristol-Myers Squibb for their long-term collaborative input which made this project possible. I would also like to acknowledge additional collaborators that have been helpful in moving this project forward: Drs. Arthur Christopoulos and Meritxell Canals from University of Monash, Drs. Brian Kobilka and Aashish Manglik from Stanford University, and Dr. Roger Sunahara from University of California-San Diego. I am also grateful for the sources of funding that have supported my graduate studies and thesis work including the Program in Biomedical Sciences (University of Michigan), the Endowment for the Basic Sciences (University of Michigan), the NIDA Neuroscience Training Program (NIH T32 DA7281-17), the Substance Abuse Interdisciplinary Training Grant (NIH T32 DA007267), and the Department of Pharmacology (University of Michigan) as well as the administration who helped arrange these fellowships and other details outside of the science including: Josh Daniels, Eileen Ferguson, Denise Gakle, Lisa Garber, Nancy Katon, Dar-Weia Liao, Dennis Ondreyka, and Ingrid Shriner-Ward. ii Table of Contents Acknowledgements ........................................................................................................... ii List of Figures .................................................................................................................... v List of Tables .................................................................................................................. viii List of Appendices ............................................................................................................ ix List of Abbreviations ........................................................................................................ x Abstract ............................................................................................................................ xii CHAPTER 1: General Introduction ............................................................................... 1 OPIOID RECEPTORS ............................................................................................................ 1 RECEPTOR THEORY ........................................................................................................... 4 CELLULAR CONSEQUENCES OF MU OPIOID RECEPTOR ACTIVATION ................................... 6 BIASED AGONISM AND IMPLICATIONS FOR NOVEL OPIOID THERAPEUTICS ......................... 8 ALLOSTERY AT OPIOID RECEPTORS ................................................................................... 9 HYPOTHESIS AND AIMS ................................................................................................... 11 CHAPTER 2: Disruption of Na+-Ion Binding Site as a Mechanism of Positive Allosteric Modulation of the Mu Opioid Receptor ...................................................... 14 SUMMARY ....................................................................................................................... 14 INTRODUCTION ............................................................................................................... 15 RESULTS ......................................................................................................................... 16 DISCUSSION ..................................................................................................................... 30 MATERIALS AND METHODS ............................................................................................. 36 CHAPTER 3: Two Chemically Distinct Allosteric Modulators Bind to a Conserved Site on Mu and Delta Opioid Receptors ....................................................................... 38 SUMMARY ....................................................................................................................... 38 INTRODUCTION ............................................................................................................... 39 RESULTS ......................................................................................................................... 41 DISCUSSION ..................................................................................................................... 49 MATERIALS AND METHODS ............................................................................................. 54 CHAPTER 4: Stabilization of Active-State Mu Opioid Receptor by Orthosteric and Allosteric Ligands: Implications for Agonist Efficacy ................................................ 58 SUMMARY ....................................................................................................................... 58 INTRODUCTION ............................................................................................................... 58 RESULTS ......................................................................................................................... 61 DISCUSSION ..................................................................................................................... 71 iii MATERIALS AND METHODS ............................................................................................. 75 CHAPTER 5: A Biased Mu-Opioid Receptor Positive Allosteric Modulator that Does Not Alter Morphine-Mediated Desensitization ............................................................ 78 SUMMARY ....................................................................................................................... 78 INTRODUCTION ............................................................................................................... 79 RESULTS ......................................................................................................................... 81 DISCUSSION ..................................................................................................................... 86 MATERIALS AND METHODS ............................................................................................. 92 CHAPTER 6: Discussion and Future Directions ......................................................... 96 FUTURE DIRECTIONS ....................................................................................................... 97 OVERALL CONCLUSIONS ............................................................................................... 103 APPENDICES ............................................................................................................... 104 BIBLIOGRAPHY ......................................................................................................... 157 iv List of Figures CHAPTER 1 Figure 1.1: Structures of various opioid ligands and crystal structures of inactive and active MOPr ........................................................................................................... 3 Figure 1.2: Sodium binding site collapses in active state of A2AAR ........................... 7 CHAPTER 2 Figure 2.1: Structure of BMS-986122 ....................................................................... 15 Figure 2.2: Structure of opioid ligands....................................................................... 18 Figure 2.3: Comparison of the effect of BMS-986122 on Met-Enk and morphine .. 19 Figure 2.4: Affinity of morphine to bind MOPr is unaltered, even in the presence of 30 µM BMS-986122 ............................................................................................. 22 Figure 2.5: Buprenorphine stimulation of G protein is concentration-dependently increased by BMS-986122 .................................................................................... 24 Figure 2.6: BMS-986122 enhances the affinity and potency of (RS)-methadone
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