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A Roadmap for Development of Novel Antipsychotic Agents Based on a Risperidone Scaffold

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A Roadmap for Development of Novel Antipsychotic Agents Based on a Risperidone Scaffold Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2017 A Roadmap for Development of Novel Antipsychotic Agents Based on a Risperidone Scaffold Urjita H. Shah Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd © The Author Downloaded from https://scholarscompass.vcu.edu/etd/4804 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]. © Urjita H. Shah, 2017 All Rights Reserved A ROADMAP FOR DEVELOPMENT OF NOVEL ANTIPSYCHOTIC AGENTS BASED ON A RISPERIDONE SCAFFOLD A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by URJITA H. SHAH Bachelor of Pharmacy, University of Mumbai, India, 2012 Director: DR. RICHARD A. GLENNON, PHD PROFESSOR, AND CHAIRMAN, MEDICINAL CHEMISTRY Virginia Commonwealth University Richmond, Virginia May 2017 Acknowledgment I would like to thank my advisor Dr. Richard A. Glennon for being an excellent mentor, and for his unending support, guidance, encouragement and constant patience over the last five years. I am extremely grateful to Dr. Małgorzata Dukat for her constructive inputs and support. Thank you, Drs. Dukat and Glennon for molding me both professionally and personally. A special thank you to all the lab members over the years: Renata, Atul, Osama, Kavita, Malaika, Farhana, Supriya, Abdelrahman, Rachel, Ahmed, Umberto, Alessandro, Pallavi and Barkha for all their help, and for making the lab a great place to work in. I would like to thank Dr. Osama I. Alwassil, Dr. Kavita A. Iyer and Dr. Philip Mosier for their help with molecular modeling. I would like to express my gratitude to Dr. Javier González-Maeso for giving me the opportunity to test our compounds in his lab, and Dr. Supriya A. Gaitonde for teaching me the techniques necessary to perform radioligand binding assays. I am thankful to Drs. Javier González-Maeso and Diomedes Logothetis as well as their lab members for providing us with biological data. I would also like to thank my committee members Dr. Glen E. Kellogg and Dr. Dana E. Selley. I am grateful to the Department of Medicinal Chemistry, School of Pharmacy and Virginia Commonwealth University for giving me the opportunity to pursue this degree. ii Mom, Dad, Chintal and Dakshil, I cannot thank you enough for your unconditional love, and constant support and encouragement throughout this endeavor. Kavita and Malaika, I am fortunate to have met you both, and I am extremely thankful to the two of you for being my support system and family in Richmond. A big thank you to Manizaay and Urvi for standing by me through the best and the worst. I would also like to thank my friends Bhavi, Nidhi, Sweta and Piyusha for all the good memories, and for making Richmond feel like home. Lastly, I am thankful to my entire family for their support. iii Table of Contents Acknowledgment ......................................................................................................................... ii List of Tables ............................................................................................................................. xii List of Figures ........................................................................................................................... xiv List of Schemes ........................................................................................................................ xxii List of Abbreviations .............................................................................................................. xxiv Abstract ................................................................................................................................... xxix I. Introduction ...............................................................................................................................1 II. Background ..............................................................................................................................4 1. Schizophrenia .......................................................................................................................4 2. Theories of schizophrenia ....................................................................................................6 a. The dopamine (DA) hypothesis of schizophrenia ............................................................6 b. The serotonin (5-HT) hypothesis of schizophrenia .........................................................9 c. The glutamate (GLU) hypothesis of schizophrenia .......................................................11 d. The GABA hypothesis of schizophrenia .......................................................................15 e. The cholinergic hypothesis of schizophrenia .................................................................16 f. The adenosine hypothesis of schizophrenia ...................................................................17 g. The α-adrenoceptor hypothesis of schizophrenia ..........................................................17 iv h. The cannabinoid hypothesis of schizophrenia ..................................................................18 3. Antipsychotic agents .............................................................................................................19 a. History ...............................................................................................................................19 b. Classification.....................................................................................................................23 c. Typical versus atypical antipsychotic agents ....................................................................25 d. Newer concepts .................................................................................................................27 i. Serotonin-dopamine antagonists ...................................................................................27 ii. Role of inverse agonists in antipsychotic activity ........................................................29 iii. Dopamine stabilizing agents .......................................................................................30 4. Serotonin receptors ..............................................................................................................32 a. 5-HT2A receptors ..............................................................................................................35 5. Metabotropic glutamate receptors........................................................................................37 a. Group II mGlu receptors: mGlu2 and mGlu3 receptors ...................................................38 6. Role of the 5-HT2A-mGlu2 receptor heteromer ...................................................................41 III. Specific aims ............................................................................................................................43 IV. Approach, results and discussion .............................................................................................53 A. Specific Aim 1. Deconstruction of risperidone to determine the minimal structural features responsible for its 5-HT2A receptor antagonist activity .......................................................53 1. Approach ....................................................................................................................... 53 2. Results ............................................................................................................................ 60 v A. Chemistry ..................................................................................................................60 B. Radioligand binding studies .......................................................................................70 C. Functional activity studies ..........................................................................................72 3. Discussion ......................................................................................................................74 B. Specific Aim 2. Elaboration of risperidone to investigate the role of the two halves of risperidone in its 5-HT2A receptor antagonist activity. ......................................................76 1. Approach .......................................................................................................................76 2. Results ............................................................................................................................84 A. Chemistry ..................................................................................................................84 B. Radioligand binding studies .....................................................................................103 C. Functional activity studies........................................................................................105 3. Discussion ...................................................................................................................107 C. Specific Aim 3. Molecular modeling studies of risperidone and its deconstructed and elaborated analogs at 5-HT2A receptors to study their binding modes. ...........................109 1. Approach ......................................................................................................................109
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