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Information to Users INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6 " x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. University Microfilms international A Bell & Howell Information Company 300 North Zeeb Road. Ann Arbor. Ml 48106-1346 USA 313/761-4700 800/521-0600 Order Number 9211140 P a rt 1 . Design, synthesis, and structure-activity studies of molecules with activity at non-NMDA glutamate receptors: Hydroxyphenylalanines, quinoxalinediones and related molecules. P a rt 2 . Computational studies on the interaction of the dopamine amino group and amino group replacements with carboxylate anions as a model for receptor interactions Hill, Ronald Alan, Ph.D. The Ohio State University, 1991 Copyright ©1991by Hill, Ronald Alan. All rights reserved. 300 N. Zeeb Rd. Ann Arbor, MI 48106 PART 1: DESIGN, SYNTHESIS, AND STRUCTURE-ACTIVITY STUDIES OF MOLECULES WITH ACTIVITY AT NON-NMDA GLUTAMATE RECEPTORS: HYDROXYPHENYLALANINES, QUINOXALINEDIONES AND RELATED MOLECULES PART 2: COMPUTATIONAL STUDIES ON THE INTERACTION OF THE DOPAMINE AMINO GROUP AND AMINO GROUP REPLACEMENTS WITH CARBOXYLATE ANIONS AS A MODEL FOR RECEPTOR INTERACTIONS DISSERTATION Presented in Partial Fullfillment of the Requirement for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Ronald A. Hill, B.S.Chem. * * * * * The Ohio State University 1991 Dissertation Committee: Approved by Duane D. Miller, Ph.D. Robert W. Brueggemeier, Ph.D. Lane J. Wallace, Ph.D. Jan K. Labanowski, Ph.D. Duane D. Miller, Adviser College of Pharmacy Copyright by Ronald Alan Hill 1991 To Shelley, Sara, Laura, and Eric, and to the Chicken Pox, without which my graduate career would have been infinitely less stimulating... ACKNOWLEDGEMENTS I would like to express my thanks to the following people: Professor Duane D. Miller, for his guidance and encouragement, and for his forbearance in allowing me to pursue many intellectual interests, to be creative (occasionally), make mistakes (more often), and in the process of it all become a better scientist. Dr. Jan K. Labanowski, also for his monumental guidance and patience, and for his good sense of humor which was often a necessity. The members of my dissertation committee, Dr. Miller, Dr. Labanowski, Dr. Breuggemeier, and Dr. Wallace. Professors Lane J. Wallace and Norman J. Uretsky, for many inspiring pharmacology discussions and tolerance of my many naive questions and observations. Dr. Jan Andzelm of Cray Research, Inc., without whose collaboration Part 2. of this thesis would be of substantially less worth. Dr. Lane Wallace, Rick Layer, Henry Tai, David Weinstein, Donna Supko, and David Willins, for their work on the pharmacological evaluation of the many compounds submitted to them. Dr. Shaun D. Black, who graciously allowed me the use of his laboratory, computers, and instrumentation, and supplied large quantities of high purity water for our HPLC systems. Jack Fowble and John Miller, who were "instrumental" in my chemistry efforts, and Bruce Posey, who provided key computer support. Joan Dandrea and Carol Settles, whose contributions are far too numerous to mention here. Kathy Brooks, Karen Patrick, and Jessica Pritchard, for their hard work in securing my paychecks (very important!), assisting with travel to meetings, and answering difficult questions. David Heisterberg and other staff members at the Ohio Supercomputer Center who provided assistance on the dopamine project and grudgingly put up with my frequent overindulgence in disk storage space on the Cray. Professors Robert Curley, Shaun Black, Raymond Doskotch, Robert Breuggemeier, Carter Olson, Alfred Staubus, Lane Wallace, Norman Uretsky, Jessie Au, Larry Robertson, Donald Witiak, Albert Soloway, and Dennis Feller, for sharing their knowledge, giving advice, providing support and assistance in securing scholarships and a job, and for making the College of Pharmacy a good place to team and do research. My research group colleagues and partners in crime, Seoung-Soo Hong, Yasser Ab-del Ghani, Katsuhisa Matsumoto, Jeff Christoff, Marc Harrold, Men Slavika, Akihiko Hamada, Yoshiya Amemiya, Vimon Tantishaiyakul, Mike Smar, and Carl Neidert, for their knowledge, encouragement, companionship, assistance, advice, support, and patience. My students, for making me a better teacher and a better person. The Ohio State University and the American Foundation for Pharmaceutical Education, without whose financial support this endeavor would have been impossible. Most importantly, my wife, who grudgingly accepted the necessity of this venture in the greater workings of die universe and took on many of my responsibilities in managing a household; my children, who somehow endured it all; and my parents, for their support and encouragement. VITA March 30,1960 Bom - Athens, Ohio, USA. June-August 1980 Chemistry Assistant (GS-IV) Physical Sciences Laboratory Newark Aerospace Guidance and Metrology Center, Newark, OH May-August 1981 Chemist The Arcanum Corporation, Ann Arbor, MI May, 1982 B.S. Chemistry, University of Michigan, Ann Arbor, Michigan. May 1982 - Sep. 1986 Research Chemist The Upjohn Company, Kalamazoo, MI Sep. 1986 - Aug. 1987 University Fellow, The Ohio State University, Columbus, OH Sep. 1987 - Aug. 1988 Graduate Teaching Fellow The Ohio State University Sep. 1988 - Present Fellow of the American Foundation for Pharmaceutical Education and Graduate Research Associate, The Ohio State University Sep. 1991 - Present Assistant Professor of Medicinal Chemistry School of Pharmacy, Northeast Louisiana University Monroe, LA PUBLICATIONS Ronald A. Hill, Jan K. Labanowski, David J. Heisterberg, Duane D. Miller, "Formic Acid: Methylamine Complex Studied by the Hartree-Fock and Density Functional Approach", in Density Functional Methods in Chemistry (Springer-Verlag, New York, 1991) pp. 357-372. R. A. Hill, B. G. Snider, and T. W. Rosanske, "A widely applicable automated sampling apparatus for dissolution testing", International Journal of Pharmaceutics, 36 (1987) 175-183. S. R. Cox, E. L. Harrington, R. A. Hill, V. J. Capponi, and A. C. Shah, "Bioavailability Studies with Ciglitazone in Beagles. 1. Effect of a Meal on the Bioavailability of Three Ciglitazone Dosage Forms", Biopharm. and Drug Dispos., 6 (1985) 67-80. FIELD OF STUDY Major Field: Pharmacy Studies in: Organic Medicinal Chemistry - Professor Duane D. Miller Computational Chemistry - Professors Duane D. Miller and Dr. Jan K. Labanowski TABLE OF CONTENTS DEDICATION ii ACKNOWLEDGEMENTS iii VITA v TABLE OF CONTENTS vii LIST OF TABLES x LIST OF FIGURES xiii LIST OF SCHEMES xviii PART 1: DESIGN, SYNTHESIS, AND STRUCTURE-ACTIVITY STUDIES OF MOLECULES WITH ACTIVITY AT AMPA GLUTAMATE RECEPTORS: HYDROXYPHENYLALANINES AND RELATED COMPOUNDS CHAPTER I. INTRODUCTION 2 1.1 Background 2 1.2 Endogenous excitatory amino acid transmission 4 1.2.1 Identification of EAA neurotransmitters 4 1.2.2 Receptor classification, physiology, and distribution 8 1.2.3 Metabolism of excitatory amino acids 19 1.2.4 Storage, release, and reuptake of EAA transmitters 2 2 1.3 Structure-activity relationships 24 1.3.1 NMDA receptors 24 a. Agonists 24 b. Competetive antagonists 26 c. Noncompetetive antagonists 28 1.3.2 Kainate receptors 30 a. Agonists 30 b. Antagonists 31 1.3.3 AP4 receptors 32 1.3.4 Metabotropic (ACPD) receptors 32 1.4 Excitatory amino acid toxicity 33 1.5 Therapeutic potential for excitatory amino acid modulation 37 H. STATEMENT OF THE PROBLEM AND OBJECTIVES 39 vii HI. CHEMISTRY 53 3.1 Hydroxyphenylalanines and related compounds 53 3.1.1 Substituted o-tyrosines 53 3.1.2 Mononitro- and dinitro-w-tyrosines 63 3.1.3 Chiral synthesis of dinitro-o-tyrosine 70 3.2 Willardiine and 5-nitrowillardiine 71 3.3 2,3-Quinoxalinediones 75 3.4 pKa studies 93 IV. DISCUSSION OF BIOLOGICAL FINDINGS 98 4.1 Hydroxyphenylalanines and related compounds 98 4.2 Structure-activity studies of 1,4-dihydro- 2,3-quinoxalinediones 108 4.3 Potential link to flavin metabolism 112 V. EXPERIMENTAL 114 5.1 General procedures 114 5.2 pKa determinations 115 5.3 Synthesis of hydroxyphenylalanines and related compounds 116 5.4 Synthesis of 2,3-quinoxalinediones and related compounds 131 PART 2: COMPUTATIONAL STUDIES ON THE INTERACTION OF THE DOPAMINE AMINO GROUP AND AMINO GROUP REPLACEMENTS WITH CARBOXYLATE ANIONS AS A MODEL FOR RECEPTOR
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