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Elaboration and Design of Α7 Nachr Negative Allosteric Modulators Osama I Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2015 Elaboration and Design of α7 nAChR Negative Allosteric Modulators Osama I. Alwassil [email protected] Follow this and additional works at: http://scholarscompass.vcu.edu/etd Part of the Medicinal and Pharmaceutical Chemistry Commons, Medicinal Chemistry and Pharmaceutics Commons, Pharmaceutics and Drug Design Commons, and the Pharmacology Commons © The Author Downloaded from http://scholarscompass.vcu.edu/etd/3902 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]. ! ! © Osama Ibrahim Alwassil 2015 All Rights Reserved ! ! ELABORATION AND DESIGN OF α7 nAChR NEGATIVE ALLOSTERIC MODULATORS A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University By OSAMA IBRAHIM ALWASSIL Bachelor of Science in Pharmaceutical Sciences, Riyadh, Saudi Arabia 2005 Master of Science in Pharmaceutical Sciences, Virginia Commonwealth University 2012 Director: MAŁGORZATA DUKAT Associate Professor, Department of Medicinal Chemistry Virginia Commonwealth University Richmond, Virginia June 2015 ii! ! Acknowledgment I would like to express my deep appreciation and respect to my advisor Dr. Małgorzata Dukat for her support, guidance, and patience. She not only taught me to be a good scientist but also to be a good person. She has made me a better person and I will remember her all through my life. I am indebted to her for all the skills that I learned during the years I spent in her laboratory. I would like to gratefully and sincerely thank Dr. Richard Glennon for the immense help and constructive comments. It was a great honor to learn from him how to question thoughts and express ideas. My great appreciation goes to Drs. Galya Abdrakhmanova and Marvin Schulte as well as their groups for providing electrophysiological data. I would also like to thank Dr. Glen Kellogg for the helpful discussion about HINT and cavity assessments in my research. I also want to thank Dr. Hardik Parikh and Dr. Saheem Zaidi. Also, I would like to thank Dr. Philip Mosier for being my trainer of molecular modeling. A special thanks for Dr. Renata Kolanos for her help and guidance with synthetic problems. I would also like to thank all lab members: Dr. Umberto Battisti, Abdelrahman Shalabi, Farhana Sakloth, Kavita Iyer, Malaika Argade, Melissa Barnier, Rachel Davis, Supriya Gaitonde, and Urjita Shah for enriching my time both as colleagues and friends. I would like to thank my committee members Dr. Richard Glennon, Dr. Glen Kellogg, Dr. Imad Damaj, Dr. Scott Gronert, and Dr. Michael Hindle. Finally, and most importantly, I would like to thank my family who are always by my side throughout the path of pursuing my dream. iii! ! Table of Contents List of Tables. ............................................................................................................................... vii List of Figures ............................................................................................................................... ix List of Schemes. .......................................................................................................................... xvii List of Abbreviations. ................................................................................................................ xviii Abstract. ..................................................................................................................................... xxii I. Introduction. ............................................................................................................................... 1 II. Background. .............................................................................................................................. 5 A. Cholinergic Receptors. ................................................................................................... 5 B. α7 nAChR Agonists. .................................................................................................... 12 C. α7 nAChR Antagonists. ................................................................................................ 14 1. Competitive Antagonists. ................................................................................ 15 a. Peptides. .............................................................................................. 15 b. Methyllycaconitine. ............................................................................ 16 c. Memantine. ......................................................................................... 17 iv! ! 2. Non-Competitive Antagonists ........................................................................ 18 D. Positive Allosteric Modulators ..................................................................................... 19 1. Extracellular Domain (ECD) PAMs ………………………………………….21 a. Galantamine ........................................................................................ 21 b. Physostigmine ..................................................................................... 22 2. Transmembrane Domain (TMD) PAMs…………………………………….24 a. PNU-120596 ....................................................................................... 24 b. Ivermectin ........................................................................................... 24 E. Negative Allosteric Modulators ................................................................................... 25 F. Clinical Implications of α7 nAChR Ligands ................................................................ 41 1. Alzheimer’s Disease……………….………………………………………….41 2. Maijuana Addiction…………….……………….……………….……………42 3. Depression…………….……………….……………….…………………..…43 4. Lung Cancer…….…….……………….……………….…………………..…45 G. Molecular Characteristics of Human α7 nAChRs ........................................................ 46 H. Previously Reported Molecular Models of Human α7 nAChRs .................................. 49 III. Specific Aims ......................................................................................................................... 52 A. QSAR. .......................................................................................................................... 53 B. Topliss Tree. ................................................................................................................. 58 C. Role of the Guanidine Nitrogen Atoms. ....................................................................... 61 D. Molecular Modeling. .................................................................................................... 63 1. Homology Modeling and Docking Studies………..………………………….63 2. Crystal Structures of Guanidines………..…………………………………….64 v! ! ! IV. Results and Discussion. ......................................................................................................... 67 A. Synthesis .................................................................................................................... 67 B. Biological Data .......................................................................................................... 74 1. QSAR ......................................................................................................... 76 2. Topliss Tree ................................................................................................ 85 3. Role of Nitrogen Atoms ............................................................................. 88 C. Molecular Modeling .................................................................................................. 91 1. Sequence Alignment and Homology Modeling ......................................... 91 2. Crystal Structures of Guanidines ................................................................ 94 3. Allosteric Binding Site Exploration ........................................................... 97 4. Docking Studies and Hydropathic Analyses .............................................. 99 D. Pharmacophore for Arylguanidines as α7 nAChR NAMs ...................................... 105 V. Conclusions ........................................................................................................................... 115 VI. Experimental ........................................................................................................................ 120! A. Synthesis .................................................................................................................. 120 N-Methyl-3-trifluoromethylaniline Nitrate (37) .......................................... 121 N-Isopropyl-N-phenylguanidine Nitrate (38) .............................................. 121 N-(3-Chlorophenyl)-N-isopropylguanidine Hydrochloride (39) ................. 122 N,N'-Di(3-trifluoromethylphenyl)urea (45) ................................................. 122 vi! ! Ethyl N-[3-(trifluoromethyl)phenyl] Carbamate (46) ................................. 122 N-Methyl-3-trifluoromethylaniline Hydrochloride (47) ............................. 123 3-Chloro-N-isopropylaniline (51) ................................................................ 124 N-Ethyl-N-phenylguanidine Hydrochloride (52) ........................................ 124 N-(3-Chlorophenyl)-N-ethylguanidine
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