Novel Analogs of M-Chlorophenylguanidine As 5-HT3 Receptor Ligands

Novel Analogs of M-Chlorophenylguanidine As 5-HT3 Receptor Ligands

Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2009 Novel Analogs of m-Chlorophenylguanidine as 5-HT3 Receptor Ligands Katie Alix 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/1734 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]. © Katie Elizabeth Alix 2008 All Rights Reserved NOVEL ANALOGS OF m-CHLOROPHENYLGUANIDINE AS 5-HT3 RECEPTOR LIGANDS A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. by KATIE ELIZABETH ALIX Bachelor of Science in Biochemistry, Virginia Tech 2006 Bachelor of Arts in Chemistry, Virginia Tech 2006 Director:MAŁGORZATA DUKAT Associate Professor, Department of Medicinal Chemistry Virginia Commonwealth University Richmond, Virginia May 2009 Acknowledgement First, I would like to thank Dr. Dukat for her patience and guidance over the last three years. She has helped mold me into a better scientist with a deeper understanding and appreciation of medicinal chemistry as an entire discipline. I would like to thank Dr. Richard Glennon for his help with my thesis and numerous useful insights. I would also like to thank Dr. Richard Young, Jessica Worsham, and Genevieve Sirles for teaching me how to handle mice and the various animal assays. I would also like to thank Dr. Jin- Sung Kim, Dr. Eliseu De Oliveria, Dr. Nadezhda German, and Dr. Mikhail Bonderov for their guidance with synthetic problems and a special thanks to Dr. Mikhail Bonderov for his help using the HPLC system. I would like to thank Justin Elenewski and Dr. Phil Moiser for their help with molecular modeling. I would like to thank my committee members Dr. Richard Glennon, Dr. Richard Young, and Dr. Aron Lichtman. And a special thank you to Shawquia Young for the synthesis of analog 48 and Samantha Casterlow for the synthesis of analogs 43 and 44 used throughout these studies. These studies were supported by the Jeffress Memorial Trust RG-J-778. I would also like to thank my loving husband for his support and confidence in me throughout this endeavor. I would like to thank the rest of my family as well for their moments of inspiration and motivation and for always being there. ii iii Table of Contents List of Tables .................................................................................................................... vii List of Figures .................................................................................................................. viii List of Schemes ................................................................................................................. xii List of Abbreviations ....................................................................................................... xiii Abstract ..............................................................................................................................xv I. Introduction ......................................................................................................................1 II. Background .....................................................................................................................4 A. History of Serotonin ............................................................................................4 B. Classification of 5-HT Receptors ........................................................................5 1. G-Protein Coupled-Receptors ..................................................................6 2. Ligand-Gated Ion-Channel Receptors .....................................................7 C. 5-HT3 receptors ...................................................................................................9 1. Classification............................................................................................9 2. Structure and Distribution ......................................................................11 3. Pharmacology and Biological Functions ...............................................12 4. Agonists .................................................................................................17 5. Antagonists ............................................................................................24 6. Quantitative Structure-Activity Relationships .......................................26 7. Behavioral Assays for Antidepressants .................................................29 8. Locomotor Activity Assay .....................................................................31 III. Specific Aims and Rationale ........................................................................................33 iv IV. Results and Discussion ................................................................................................43 A. Halogen Series ..................................................................................................43 1. Synthesis of N-(3-Fluorophenyl)guanidine Nitrate (42) ........................43 2. Binding Studies ......................................................................................44 3. Hansch Analysis.....................................................................................46 4. Log P Analysis .......................................................................................52 5. Molecular Modeling...............................................................................56 6. Designed Ligand ....................................................................................67 B. Conformationally-Constrained Analogs ...........................................................68 1. Synthesis of 2-Amino-7-chloro-3,4-dihydroquinazoline (46) ...............68 2. Synthesis of 2-Amino-6-chloro-3,4-dihydroquinazoline (47) ...............69 3. Binding Studies ......................................................................................70 4. Log P Analysis .......................................................................................71 5. Behavioral Studies .................................................................................73 a. Tail Suspension Test ..................................................................73 b. Locomotor Activity Assay .........................................................79 6. Molecular Modeling...............................................................................84 7. Synthesis of 2-Amino-8-chloro-1,3-benzodiazepine (49) .....................88 V. Conclusions ...................................................................................................................94 VI. Experimental ..............................................................................................................100 A. Synthesis .........................................................................................................100 N-(3-Fluorophenyl)guanidine, Nitrate (42) .............................................100 2-Amino-7-chloro-3,4-dihydroquinazoline, Hydrochloride (46) ............101 2-Amino-6-chloro-3,4-dihydroquinazoline, Hydrochloride (47) ............102 N-(3-Chloro-4-hydroxyphenyl)guanidine, Hydrochloride (51) ...............103 v 2-Chloro-4-nitrophenol (53) ....................................................................103 3-Chloro-4-hydroxyaniline, Hydrochloride (54) .....................................104 2-Amino-7-chloro-quinazolin-4-(3H)-one (56) .......................................104 2-Amino-6-chloro-quinazolin-4-(3H)-one (58) .......................................105 2-Amino-4-chlorobenzylalcohol (60, R = H) ..........................................105 2-Amino-4-chlorobenzylbromide (61, R = H) ........................................106 2-(2-Amino-4-chlorophenyl)acetic Acid (65) ..........................................106 4-Chloro-2-nitrobenzaldedhyde (69) .......................................................107 4-Chloro-2-nitro-1-(2-nitrovinyl)benzene (70) ........................................108 (4-Chloro-2-nitrophenyl)(1H-imidazol-1-yl)methanone (72) .................108 4-Chloro-2-nitrobenzylbromide (75) .......................................................109 2,3-Bis(4-chloro-2-nitrophenyl)propanenitrile (77) ................................109 B. Log P Analysis ................................................................................................111 1. Standards ..............................................................................................111 2. Halogen Series .....................................................................................113 3. Quinazoline Series ...............................................................................113 C. Behavioral Studies ...........................................................................................114 1. Animals ................................................................................................114 2. Drugs ....................................................................................................115 3. Tail Suspension Test ............................................................................115 4. Locomotor Activity Assay ...................................................................117

View Full Text

Details

  • File Type
    pdf
  • Upload Time
    -
  • Content Languages
    English
  • Upload User
    Anonymous/Not logged-in
  • File Pages
    157 Page
  • File Size
    -

Download

Channel Download Status
Express Download Enable

Copyright

We respect the copyrights and intellectual property rights of all users. All uploaded documents are either original works of the uploader or authorized works of the rightful owners.

  • Not to be reproduced or distributed without explicit permission.
  • Not used for commercial purposes outside of approved use cases.
  • Not used to infringe on the rights of the original creators.
  • If you believe any content infringes your copyright, please contact us immediately.

Support

For help with questions, suggestions, or problems, please contact us