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A Study of the Action of Risperidone at 5-HT2A Receptors Supriya A

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A Study of the Action of Risperidone at 5-HT2A Receptors Supriya A Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2016 A study of the action of risperidone at 5-HT2A receptors Supriya A. Gaitonde Virginia Commonwealth University, [email protected] Follow this and additional works at: http://scholarscompass.vcu.edu/etd Part of the Medicine and Health Sciences Commons © The Author Downloaded from http://scholarscompass.vcu.edu/etd/4112 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]. © Supriya Gaitonde 2016 All Rights Reserved A STUDY OF THE ACTION OF RISPERIDONE AT 5-HT2A RECEPTORS A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by SUPRIYA A. GAITONDE Bachelor of Pharmaceutical Science, University of Mumbai, India, 2011 Director: DR. MAŁGORZATA DUKAT, PH.D. ASSOCIATE PROFESSOR, DEPARTMENT OF MEDICINAL CHEMISTRY Co-Director: DR. RICHARD A. GLENNON, PH.D. PROFESSOR AND CHAIRMAN, DEPARTMENT OF MEDICINAL CHEMISTRY Virginia Commonwealth University Richmond, Virginia April 2016 ii Acknowledgement I would like to sincerely thank my advisors, Dr. Małgorzata Dukat and Dr. Richard A. Glennon for their contribution in my life during my years as a graduate student in their laboratory. I will be forever indebted to them for their constant patience and support, especially during my initial years in the lab, and that has gone a long way in helping me both, personally and professionally. I would like to thank all my lab colleagues who have become good friends over the years: Kavita, Malaika, Urjita, Osama, Farhana, Renata, Umberto, Rachel and Abdelrehman. I will always cherish the time spent in lab, especially lunchtime and the routine walk to Starbucks with Kavita, Malaika and Urjita. I would like to thank them for all the help and support in lab. A special thanks to Dr. Osama Alwassil for his help and guidance with molecular modeling. I would like to thank Dr. Javier González-Maeso for all his help with the radioligand binding data, and also my committee members Dr. Glen E. Kellogg, Dr. Diomedes E. Logothetis and Dr. Dana E. Selley. I would like to thank my best friends: Amrita, Debolina, Anuya, Neha Gangal, and Manasi for being with me through thick and thin. I want to thank my parents, who have been with me through every step of this journey, and my husband Hitesh, who has been a great support system. This wouldn’t have been possible without their constant love, support and encouragement. iii Table of Contents Page Acknowledgements ............................................................................................................. ii List of Tables ................................................................................................................... viii List of Figures ..................................................................................................................... ix List of Schemes ................................................................................................................. xiv List of Abbreviations ......................................................................................................... xv Abstract ........................................................................................................................... xxii Chapter I Introduction ....................................................................................................................... 1 II Background ...................................................................................................................... 4 A. Mental health and the world ........................................................................................ 4 1. Current status of mental health in the world ............................................................ 4 2. An overview of antipsychotic therapy in the United States ..................................... 8 3. Are antipsychotics helpful in the long run? ........................................................... 11 4. Therapeutic strategies and those under development ............................................ 13 B. Conditions associated with serotonin imbalance ....................................................... 19 1. Psychosis due to 5-HT agonists and/or hallucinogens ........................................... 21 2. Depression ............................................................................................................ 24 iv 3. Anxiety disorders ................................................................................................... 26 4. Schizophrenia ........................................................................................................ 29 a. Symptoms and neuroanatomical changes ......................................................... 31 b. The dopamine hypothesis of schizophrenia ...................................................... 34 c. The serotonin hypothesis of schizophrenia ....................................................... 36 d. The NMDA hypofunction/ glutamate hypothesis…………………………….38 C. The 5-HT class of receptors ....................................................................................... 39 1. 5-HT2A receptors and some ligands targeting them ............................................... 42 2. The 5-HT2A-mGlu2 heteromer ............................................................................... 44 III Specific aims ................................................................................................................ 46 IV Approach, results and discussion .................................................................................. 59 A. Deconstruction of risperidone ................................................................................... 59 1. Approach ................................................................................................................ 59 2. Results .................................................................................................................... 64 a. Chemistry .......................................................................................................... 64 b. Functional activity studies ................................................................................ 70 c. Radioligand binding studies .............................................................................. 81 3. Discussion .............................................................................................................. 84 B. Elaboration of risperidone .......................................................................................... 87 1. Approach ................................................................................................................ 87 2. Results .................................................................................................................... 92 a. Chemistry .......................................................................................................... 92 v b. Functional activity studies ................................................................................ 99 c. Radioligand binding studies ............................................................................ 101 3. Discussion ............................................................................................................ 104 C. Molecular modeling studies ..................................................................................... 106 1. Approach .............................................................................................................. 106 2. Results and discussion ......................................................................................... 110 V Conclusion ................................................................................................................... 130 VI Experimentals ............................................................................................................. 137 A. Synthesis .................................................................................................................. 137 6-Fluoro-3-(piperidin-4-yl)benz[d]isoxazole hydrochloride (55) ........................... 138 4-(4-(6-Fluorobenz[d]isoxazol-3-yl)piperidin-1-yl)-1-(piperidin-1 yl)butan-1-one hydrochloride (56) ................................................................................................... 138 6-Fluoro-3-(1-(4-(piperidin-1-yl)butyl)piperidin-4-yl)benz[d]isoxazole hydrochloride (57) .................................................................................................. 139 6-Fluoro-3-(1-methylpiperidin-4-yl)benz[d]isoxazole hydrochloride (58) ............. 140 (±)4-(4-(6-Fluorobenz[d]isoxazol-3-yl)piperidin-1-yl)-1-(3-hydroxypiperidin-1- yl)butan-1-one hydrogen oxalate (59) ..................................................................... 141 3-(Piperidin-4-yl)-1,2-benz[d]isoxazole hydrochloride (60) ................................... 142 3-(1-Methylpiperidin-4-yl)benz[d]isoxazole hydrochloride (61) ............................ 142 4-Chloro-1-(piperidin-1-yl)butan-1-one (67) .......................................................... 143 (±)4-Chloro-1-(3-hydroxypiperidin-1-yl)butan-1-one (74) ..................................... 143 1-Formylpiperidine-4-carboxylic
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