Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2019 Structure-Activity Relationship Studies of Synthetic Cathinones and Related Agents Rachel A. Davies Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medicinal and Pharmaceutical Chemistry Commons, Medicinal Chemistry and Pharmaceutics Commons, Molecular and Cellular Neuroscience Commons, Organic Chemicals Commons, Other Psychiatry and Psychology Commons, Pharmacology Commons, and the Substance Abuse and Addiction Commons © Rachel A. Davies, 2019 All Rights Reserved Downloaded from https://scholarscompass.vcu.edu/etd/5953 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Rachel A. Davies, 2019 All Rights Reserved i STRUCTURE ACTIVITY RELATIONSHIP STUDIES OF SYNTHETIC CATHINONES AND RELATED AGENTS A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medicinal Chemistry at Virginia Commonwealth University. By RACHEL A. DAVIES Bachelor of Science, Middle Tennessee State University, United States, 2013 Director: DR. GLENNON PROFESSOR DEPARTMENT OF MEDICINAL CHEMISTRY Virginia Commonwealth University Richmond, Virginia July, 2019 ii Acknowledgements I begin by acknowledging my mentor Dr. Richard Glennon, as well as Dr. Malgorzata Dukat, for their investments of time and resources in my development as an academic. I most appreciate both of their high standards and expectations, which I believe have helped me grow professionally and become a more resilient person. I look forward to joining the ranks of the distinguished alumni of the Glennon/Dukat group. When it comes to technical training, I first acknowledge Dr. Umberto Battisti for the training in organic synthesis. I hope to emulate in my future endeavors the leadership he exemplified as a post-doctoral researcher and laboratory manager. Dr. Glen Kellogg, Dr. Philip Mosier, and Claudio Catalano provided considerable assistance in computational modeling. Claudio in particular spent considerable time assisting me. Dr. Jose Eltit trained me in cell culture and calcium imaging, supported me in developing the pharmacology aspect of my project, and taught me how to effectively manage time to complete experimental investigations. My committee members present and former, including Dr. Katherine Nicholson, Dr. Richard Young, and Dr. Javier Gonzales-Maeso, are to be thanked for their investment of time and expertise in my education. Dr. Chris Kelly provided provocative counsel on organic reaction mechanisms. Suggestions from these faculty to improve this work have been essential. I was very fortunate to join the synthetic cathinone project and Glennon/Dukat laboratory at an exciting time, in the midst of a collaboration between physiology, pharmacology, and medicinal chemistry. Everyone involved in this project enhanced the development of my work. Our weekly meetings were enriching and I am grateful to have participated. Firstly, I would like to thank Dr. Louis J. De Felice, and may he rest in peace. I will never forget his warm nature or his creative mind. Dr. Jose Eltit’s group, particularly Vy Nguyen, and also Brian Ruiz, iii contributed immensely to this work. Dr. Steve Negus and his laboratory, as well as Dr. Michelle Peace and her forensics team, especially Tyson Baird, should also be acknowledged for their contributions to this project. Additionally, the animals used in the course of these investigations are hereby acknowledged for their sacrifices. I have shared the Glennon/Dukat lab with many scholars over the years, including Dr. Osama I. Alwassil, Dr. Farhana T. Sakloth, Dr. Supriya A. Gaitonde, Dr. Kavita Iyer, Dr. Abdelrahman E. S. Shalabi, Ahmed S. Abdel Khalek, Dr. Malaika D. Argade, Dr. Urjita H. Shah, Alessandro Magueri, and Preeth Hemanth. I must specially recognize Pallavi Nistala and Dr. Barkha Yadav, both of whom went above and beyond what is expected of any lab mate or friend. On a personal note, I would like to acknowledge the contribution of my friends and community in Richmond, VA. These individuals include Celia Pringle, Thomas Bannard, Dr. Linda Hancock, Dr. Jessica Bourdon, Daniel Roh, and Dr. Kenny Kane. My closest friends in Richmond, Mike Shea and Stephen Flores, helped care for my dog as I completed this work. Erin Fowler also deserves special recognition, not only for providing close friendship, but for helping me get to the lab on time. Finally I must acknowlege those who have inspired and supported me all along: my family. Amber Burgstahler and Shane Faulkner must be credited with inspiring me by their personal triumphs. My mother, Ellen Mast, supported me in pursuing my passion, without which this work would not have been possible. To select other family and family friends, including Mattie and Jordan Watkins, Annie and Frank Dufay and Peg Justice, thank you for your love and support along this journey. Finally, I would like to thank and dedicate this dissertation to the memory of my late father, Dr. Jack Davies, who instilled in me the value of fidelity to science and truth above all else. iv Table of Contents Acknowledgements ................................................................................................................. iii List of Tables ........................................................................................................................ viii List of Figures......................................................................................................................... ix List of Schemes ....................................................................................................................... xi List of Abbreviations.............................................................................................................. xii Abstract ......................................................................................................................... xiv I. Introduction ...................................................................................................................1 II. Background ..................................................................................................................5 A. The Phenylalkylaminome ..................................................................................................... 5 1. Overview ...................................................................................................................................... 5 2. Psychoactive Classes of Phenylalkylamines ....................................................................................... 7 B. Amphetamine-Type Stimulants .......................................................................................... 10 1. The State of ATS Use and Misuse .................................................................................................. 10 2. Definitions of ATS ....................................................................................................................... 12 3. History of ATS ............................................................................................................................ 14 a. ATS Natural Products: Pharmacognosy of Khat and Ephedrine ....................................................... 14 b. Amphetamine and Early Synthetic ATS: Clinical Use and Misuse................................................... 19 c. Illicit ATS and Designer Drugs: Methamphetamine, MDA, MDMA, and Methcathinone ................... 22 d. ATS NPS: Synthetic Cathinones (2010-Present) ........................................................................... 23 i. Bath Salts ............................................................................................................................ 23 ii. α-Pyrrolidinophenones and Second-Generation “Bath Salts” ...................................................... 24 C. Monoamines and their Transporters .................................................................................. 25 1. Monoaminergic Neurotransmission ................................................................................................. 25 a. Overview ................................................................................................................................ 25 b. Biosynthesis ............................................................................................................................ 26 c. Monoamine Receptors .............................................................................................................. 26 d. Monoamine Degradation and Signal Termination ......................................................................... 27 e. Discovery of DA Pathways ........................................................................................................ 28 2. Monoamine Transporters: Discovery ............................................................................................... 28 3. Structure of MATs – from Cloning to Crystals and Beyond ................................................................ 30 4. Evolution of MATs....................................................................................................................... 34 5. Mechanism of Neurotransmitter Transport ......................................................................................