City University of New York (CUNY) CUNY Academic Works All Dissertations, Theses, and Capstone Projects Dissertations, Theses, and Capstone Projects 2-2016 Synthesis of Novel Aporphine-Inspired Neuroreceptor Ligands Nirav R. Kapadia Graduate Center, City University of New York How does access to this work benefit ou?y Let us know! More information about this work at: https://academicworks.cuny.edu/gc_etds/792 Discover additional works at: https://academicworks.cuny.edu This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] SYNTHESIS OF NOVEL APORPHINE-INSPIRED NEURORECEPTOR LIGANDS by Nirav R Kapadia A dissertation submitted to the Graduate Faculty in Chemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy, The City University of New York. 2016 © 2016 NIRAV R KAPADIA All Rights Reserved ii This manuscript has been read and accepted by the Graduate Faculty in Chemistry in satisfaction of the dissertation requirement for the degree of Doctor of Philosophy ____________________ _________________________ Date Dr. Wayne Harding Chair of Examining Committee ____________________ __________________________ Date Dr. Brian Gibney Executive Officer Dr. Adam Profit Dr. Shengping Zheng Dr. Wayne Harding Supervisory Committee THE CITY UNIVERSITY OF NEW YORK iii ABSTRACT Synthesis of Novel Aporphine-Inspired Neuroreceptor Ligands by Nirav R Kapadia Advisor: Dr. Wayne Harding Aporphines are a group of tetracyclic alkaloids that belong to the ubiquitous tetrahydroisoquinoline family. The aporphine template is known to be associated with a range of biological activities. Aporphines have been explored as antioxidants, anti-tuberculosis, antimicrobial and anticancer agents. Within the Central Nervous Systems (CNS), aporphine alkaloids are known to possess high affinity for several clinically valuable targets including dopamine receptors (predominantly D1 and D2), serotonin receptors (5-HT1A and 5-HT7) and α adrenergic receptors. Aporphines are also inhibitors of the acetylcholinesterase enzyme – a clinical target for the treatment of Alzheimer’s disease. Considering the diverse profile of aporphine alkaloids at CNS receptors they can be considered as “privileged scaffold” for the design of CNS drugs. The aporphine alkaloid nantenine is a 5-HT2A receptor antagonist and has moderate affinity for the 5-HT2A receptor. Selective 5-HT2A antagonists have therapeutic potential for the treatment of a number of neuropsychiatric disorders including depression, schizophrenia and sleep disorders. The aporphine core of nantenine serves as a valuable lead for the identification of selective 5-HT2A antagonists. In order to understand the structural tolerance of the aporphine core required for 5-HT2A antagonism an exhaustive Structure Activity Relationship (SAR) study was designed. Accordingly, a diverse library of nantenine analogues was synthesized and evaluated for affinity at the 5-HT2A iv receptor. Results from the SAR studies demonstrate that the nitrogen atom of nantenine is required for affinity and that introduction of a phenyl ring at the C4 position is detrimental for 5-HT2A receptor affinity. At the C3 position, introduction of halogen atoms is beneficial for 5-HT2A antagonistic activity. Furthermore, a library of C3 analogues having hydrophobic substituents as well as ring D indole analogues is currently being evaluated for affinity at the 5-HT2A receptors. These compounds will further expand our understanding of the tolerance of the aporphine core required for 5-HT2A antagonism. In order to rationalize the affinity of certain high affinity ligands, molecular docking studies were conducted. Selected compounds were docked into a homology model of the 5-HT2A receptor to extract information about possible binding modes. Based on results of these studies, it is concluded that the interaction of C3 halogenated aporphine analogues with Phe339/Phe340 residues might be responsible for their enhanced affinity. Information obtained from molecular docking studies is being utilized for design of advanced generations of analogues. Finally, a novel series of flexible tris-(phenylalkyl)amines were synthesized and evaluated to test the importance of a rigid aporphine core as well as incorporation of N-phenylalkyl substituents. These compounds featuring a halogen substituent in ring C, were found to have high affinity and selectivity for the 5-HT2B receptor, with some of the compounds being more potent than the selective 5-HT2B antagonist SB200646. Results from this study indicate that ring C of these compounds is generally tolerant for halogen substitution. The synthetic feasibility of this newly identified template (4 high-yielding synthetic steps from commercially available materials) makes this scaffold attractive for the synthesis of larger libraries of analogs and promise for optimization of 5-HT2B affinity and selectivity. v ACKNOWLEDGEMENTS Although the process of PhD terminates at the completion of a thesis, it also marks the commencement of a new scientific journey. I would like to take this opportunity to recognize and thank many people who have directly and indirectly contributed in this journey. First and foremost, I would like to thank my PhD mentor, Prof. Wayne W Harding for his mentorship. Your guidance has enabled me to successfully complete this thesis as well as helped me to evolve as a scientist. You displayed patience and confidence in me, whenever I encountered any problems. You also showed immense excitement and supported me when I had positive results. Under your mentorship, I have learned a lot about the application of modern organic chemistry in the field of drug discovery and drug design. Your discipline and passion for organic chemistry continue to inspire me. I will be forever grateful to be a part of your research group. I also thank my committee members, Prof. Shengping Zheng and Prof. Adam Profit for always providing their valuable feedback which help shaped the course of this thesis. I was fortunate to be trained by and to work alongside two highly talented post-doctoral researchers – Dr. Shashikanth Ponnala and Dr. Sudarshan Madapa. I thank both of them for having taught me as well as master me many synthetic chemistry and literature search techniques. I will be forever indebted to your assistance. I also thank the Dept. of Chemistry at Hunter College for setting up a unique and congenial research environment. A special thanks to Dr. Matthew Devany for maintaining a state of the art NMR facility. I would also like to thank Late. Dr. Cliff Soll, Dr. Srinivas Chakravartula as well as Dr. Barney Yoo for providing Mass spectrometry services. I thank Prof. Mootoo and his research vi group as well as Prof. Zheng and his research group for providing generous access to chemicals. I also appreciate the efforts put in by the Chemistry Department’s administrative and teaching staff: Ms. Mirela Settenhofer, Ms. Shontel Housten and Ms. Olena Shport - your consistent efforts always helped to reduce the impact of non-research activities on my research. This journey although difficult, was made to look easy because of the constant support of my friends. First I would like to thank my lab colleagues - Satish Gadhiya, Sujay Joseph and Sharear Ahmed for always providing me your assistance, feedback and lighter moments in the lab. A special thanks to Kriti Kalpana – you made me believe in me and gave me beautiful memories outside the lab to cherish. I thank Ashwini Goghare and Deven Patel for your help and encouragement. I also thank Zhwei Yin and Junior Gonzales for their support. Finally I am indebted to my family without whose love, support and motivation this work was impossible. I would like to thank my father, Mr. Raman Kapadia and mother Mrs. Saroj Kapadia for always instilling the importance of hard work and determination in my life. I also thank Nilesh, Hiren and Kalpana for all their help, moral support and encouragement. I could not have accomplished this without you. vii I dedicate this thesis to my parents and family. 滁 ڂમારા માતા-સિતા અને િરરવાર ને અિપણ કર ڂઆ થીસિિ હ कर्मण्येवाधिकारते र्ा फलेषु कदाचन। र्ा कर्मफलहते ुर्भमर्ाम ते सङ्गोऽ्वकर्मधि॥ २-४७ You have the right to work only but never to its fruits. Let not the fruits of action be your motive, nor let your attachment be to inaction. (Bhagwad Gita, Chapter 2, verse 47) viii TABLE OF CONTENTS ABSTRACT .................................................................................................................................. iv ACKNOWLEDGEMENTS…………………………………………………………………….vi TABLE OF CONTENTS………………………………………………………………………..ix LIST OF SYMBOLS AND ABBREVIATIONS………………………………………………xii LIST OF FIGURES .................................................................................................................. xvii LIST OF TABLES ..................................................................................................................... xxi LIST OF SCHEMES ................................................................................................................ xxii CHAPTER I: INTRODUCTION 1.1 Aporphine Alkaloids 1.1.1 Background and Occurrence………………………………………………...2 1.1.2 Biosynthesis of Aporphine Alkaloids………………………………………..2 1.1.3 Common Synthetic Approaches to Aporphine Alkaloids……………………5 1.1.4 Pharmacological Effects of Aporphine Alkaloids……………………….......8 1.2 5-HT2A Antagonists 1.2.1 Background………………………………………………………………...14 1.2.2 Clinical Significance of 5-HT2A Antagonists…............................................14