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5-HT3 Receptor Ligands and Their Effect on Psychomotor Stimulants

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5-HT3 Receptor Ligands and Their Effect on Psychomotor Stimulants Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2008 5-HT3 Receptor Ligands and Their Effect on Psychomotor Stimulants Jessica Nicole Worsham Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Chemicals and Drugs Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/1054 This Thesis 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]. © Jessica Nicole Worsham, 2008 All Rights Reserved 5-HT3 RECEPTOR LIGANDS AND THEIR EFFECT ON PSYCHOMOTOR STIMULANTS A Thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. By JESSICA NICOLE WORSHAM Bachelor of Science, Roanoke College, 2005 Director: MALGORZATA DUKAT, Ph.D. Associate Professor, Department of Medicinal Chemistry Co-Director: RICHARD A. GLENNON, Ph.D. Professor, Chairman, Department of Medicinal Chemistry Virginia Commonwealth University Richmond, Virginia May 2008 ii Acknowledgement First and foremost I would like to thank Dr. Dukat and Dr. Glennon for their guidance through the past few years. This guidance has helped me to better understand and appreciate the depth of knowledge I hope to one day attain. I also would like to thank Dr. Richard Young for his teachings on the locomotor activity assay, as well as always fixing the glitches when there was instrument failure. Much appreciation is bestowed to Dr. Eliseu De Oliveira, Dr. Renata Kolanos, and Dr. Mikhail Bondarev for their help with synthetic problems. Their help has greatly broadened my understanding of synthetic chemistry. I would like to thank Dr. Phil Mosier for his help and better understanding of molecular modeling. Special thanks to Katie Ownby and Samantha Casterlow for their synthesis of the halogenated guanidines and constrained analog used in the QSAR studies. This study was supported by Jeffress Memorial Trust RG-J-778 (MD). I would also like to show immense appreciation to my family, my mom and my dad, who have provided countless moments of inspiration and motivation to achieve my goals. I would not be the person I am today without them. I would like to thank my aunt Connie, who has provided me with encouragement from the beginning. Also, a special thanks to Genevieve Sirles, my colleague from the beginning of my endeavor for a Master’s degree, who also helped to motivate me when synthetic adversity stood in my way. iii Table of Contents Page Acknowledgements ........................................................................................................ ii Table of Contents............................................................................................................... iii List of Tables ................................................................................................................... viii List of Figures.................................................................................................................... ix List of Schemes.............................................................................................................. xviii List of Abbreviations ....................................................................................................... xix Abstract............................................................................................................................ xxi I. Introduction........................................................................................................1 II. Background........................................................................................................5 A. Drug Abuse/Drug Addiction ...................................................................5 B. Classification ...........................................................................................7 1. Opioids ...............................................................................................7 2. Stimulants...........................................................................................8 a) Analeptics......................................................................................8 b) Behavioral Stimulants...................................................................9 i. Non-Phenylalkylamines ...........................................................9 ii. Phenylalkylamines .................................................................12 3. Non-Stimulant Phenylalkylamines...................................................19 iv C. Mechanism of Action of Stimulants......................................................24 1. Dopamine .........................................................................................26 2. Norepinephrine.................................................................................31 3. Serotonin ..........................................................................................31 D. Serotonin Receptors...............................................................................32 1. Classification....................................................................................32 2. 5-HT3 Receptors...............................................................................33 a) Structure and Distribution ...........................................................33 b) Function ......................................................................................36 c) Antagonists..................................................................................36 d) Agonists ......................................................................................38 E. Quantitative Structure-Activity Relationships………………………...44 F. Behavioral Assays……………………………………………………..46 III. Specific Aims...................................................................................................49 IV. Results and Discussion....................................................................................58 A. Behavioral Studies.................................................................................58 1. Results ..............................................................................................58 a) MD-354 ........................................................................................58 b) Ondansetron .................................................................................60 c) SR 57227A ...................................................................................63 v d) (+)Amphetamine ..........................................................................66 i. Dose Response .........................................................................66 ii. Combination of (+)Amphetamine and MD-354 .....................69 iii. Combination of (+)Amphetamine and Ondansetron...............72 iv. Combination of (+)Amphetamine and SR 57227A.................75 e) (+)Methamphetamine...................................................................78 i. Dose Response .........................................................................78 ii. Combination of (+)Methamphetamine and MD-354 ...............81 f) DOM .............................................................................................84 i. Dose Response .........................................................................84 ii. Combination of DOM and MD-354.........................................87 g) Cocaine.........................................................................................91 i. Dose Response ..........................................................................91 ii. Combination of Cocaine and MD-354......................................96 iii. Combination of Cocaine and Ondansetron ...............................99 iv. Combination of Cocaine and SR 57227A ...............................104 2. Discussion.......................................................................................108 B. Synthesis..............................................................................................126 1. Preparation of phenyl carbamate analogs of MD-354.....................126 2. Preparation of a conformationally-constrained analog of vi MD-354……………………………………………………………...139 C. Molecular Modeling ............................................................................141 V. Conclusions....................................................................................................155 VI. Experimental..................................................................................................158 A. Synthesis...............................................................................................158 m-Chlorophenylguanidine nitrate (42). ...............................................158 Phenyl [[(3-chlorophenyl)amino](imino)methyl]carbamate (53).. .....159 2-Amino-7-chloro-3,4-dihydroquinazoline hydrochloride (56)..........160 2-Amino-6-chloro-3,4-dihydroquinazoline hydrochloride (57)..........161 Methyl [[(3-chlorophenyl)amino](imino)methyl]carbamate (62).......162 N,N’-bis(3-chlorophenyl)urea (64).....................................................164 N,N,N’,N’-Tetrakis(phenylcarbamate)-3-chlorphenylguanidine hydrochloride (68). ............................................................................166 2-Amino-6-chloro-4-dihydroquinazolinone (74). .............................167
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