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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 hleedthrough, 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 corner 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 9411918 Part 1. Synthesis of arylalkylguanidines as dopamine agonists. Part 2, Section A. Modifications of trimetoquinol and the effects on /3-adrenergic and thromboxane2 receptor A systems. Section B. Approaches to the asymmetric synthesis of irreversibly binding iodinated derivatives of trimetoquinol Christoff, Jeffrey James, Ph.D. The Ohio State University, 1993 300 N. Zeeb Rd. Ann Arbor, M I 48106 Part 1: Synthesis of Arylalkylguanidines as Dopamine Agonists Part 2, Section A: Modifications of Trimetoquinol and the Effects on B-Adrenergic and Thromboxane A2 Receptor Systems Section B: Approaches to the Asymmetric Synthesis of Irreversibly Binding lodinated Derivatives of Trimetoquinol Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jeffrey J. Christoff, B.S Pharm., R.Ph. * * * * * The Ohio State University 1993 Dissertation Committee: Approved by Duane D. Miller, Ph.D. Robert W. Brueggemeier, Ph.D. Duane D. Miller, Ph.D., co-advisor Larry W. Robertson, Ph.D. Dennis R. Feller, Ph.D. Robert W. Brueggemeier, Ph.D., co-advisor College of Pharmacy Dedicated to Cindy The Time is Now Ours to Share ii ACKNOWLEDGEMENTS I wish to thank: Dr. Duane D. Miller for his support and guidance throughout my graduate career. Dr. Robert W. Brueggemeier for his advice and support while serving as co-advisor. The dissertation committee for their input in preparing this document. Dr. Dennis Feller and Dr. Norman Uretsky for their collaborative efforts. Gamal Shams, Karl Romstedt, Paul Fraundorfer, Tahira Farooqui, Longping Lei, and Fernando Rodriguez for their hard work evaluating my compounds. Jill (Golder) O’Reilly for her friendship, advice and tolerance. Carl Lovely, Pat Cyr, Jeff Herndon, Kazu Matsumoto, Ron Hill, Yasser Abdel-Ghany, and Meri Slavica for their suggestions and criticisms. Nancy (Katlic) Gilbert for her expert advice and aid in preparing slides and posters. Kim Risch, Joan Dandrea, Kathy Brooks, and Carol Settles for their assistance with numerous predicaments. Jack Fowble, John Miller, and Bruce Posey for their assistance with instrumental and computer complications. Luke Bradley for his invaluable work on the Trimetoquinol project. Damon Sharp and Margie Centeno for steadily supplying me with clean glassware. Dr. B’s research group for adopting me as one of their own and tolerating synthetic organic chemistry during group meetings. The entire Division of Medicinal Chemistry and Pharmacognosy for allowing me to mooch whatever, whenever I needed it. Dr. Doskotch for his objective opinions and comments. LAGNAFs, Home Platelets, Heavily Sedated and Topliss Dancers for providing a physical and emotional diversion from work. The National Institutes of Health, American Foundation for Pharmaceutical Education, College of Pharmacy, and Graduate School for financial support. iv VITA Aug. 14, 1965 Born - Pittsburgh, Pennsylvania May 8, 1988 B.S. Pharmacy, Duquesne University Pittsburgh, Pennsylvania May 1988 - Aug. 1988 Research Intensive Summer Intern Merck, Sharp & Dohme Research Laboratories West Point, Pennsylvania Sept. 1988 - Aug. 1989 University Fellow The Ohio State University Columbus, Ohio Sept. 1988 - Oct. 1993 Academic Challenge Fellow The Ohio State University Columbus, Ohio Sept. 1989 - Aug. 1990 Graduate Teaching Assistant The Ohio State University Columbus, Ohio Sept. 1990 - Oct. 1993 Graduate Research Associate The Ohio State University Columbus, Ohio Sept. 1991 - Oct. 1993 American Foundation for Pharmaceutical Education Fellow The Ohio State University Columbus, Ohio v PUBLICATIONS AND PRESENTATIONS 1. Katdare, A.V.; Keller, K.O.; Christoff, J.J.; Bavitz, J.F. Evaluation of Dissolution Characteristics of an Encapsulated Water Soluble Tablet Granulation. Drug Dev. Ind. Pharm. 1990, 16(7), 1109-1119. 2. Christoff, J.J.; Harrold, M.W.; Miller, D.D.; Fraundorfer, P.; Romstedt, K.J.; Feller, D.R. Modification of the Trimethoxybenzyl Substituent of Trimetoquinol and its Effects on (3-Adrenergic and Thromboxane A2 Receptor Systems. Presented at the 25th Annual Graduate Student Symposium in Medicinal Chemistry, Ann Arbor, Ml, June 28-30, 1992. Session 2, First Presentation. 3. Christoff, J.J.; Miller, D.D.; Farooqui, T.; Uretsky, N. Arylalkylguanidines as Dopaminergic Agonists. Presented at the 26th Annual Graduate Student Symposium in Medicinal Chemistry, West Lafayette, IN, June 27- 29, 1993. Fifth Poster. 4. Christoff, J.J.; Miller, D.D.; Farooqui, T.; Uretsky, N. Synthesis and Biological Evaluation of Arylalkylguanidines as Dopaminergic Agonists. Presented at the 206th National Meeting of the American Chemical Society, Chicago, IL, August 22-27, 1993. Paper MEDI 170. FIELDS OF STUDY Major Field: Pharmacy Studies in : Synthetic Medicinal Chemistry vi TABLE OF CONTENTS PAGE D E D IC A T IO N ................................................................................................................ ii ACKNOWLEDGEMENTS ..................................................................................... iii VITA ........................................................................................................................ v LIST OF TABLES.................................................................................................... xi LIST OF FIGURES............................................................................................... xiii LIST OF SCHEMES............................................................................................. xvi Part 1 Synthesis of Arylalkylguanidines as Dopamine Agonists .................... 1 CHAPTER I INTRODUCTION ............................................................................................... 2 1.1 Background ............................................................................................... 2 1.2 Location and Distribution of Dopamine ................................................ 5 1.3 Dopamine Receptor Subtypes .............................................................. 7 1.4 Therapeutic Uses of Dopamine Agonists .......................................... 11 1.5 Classifications of Dopamine A g o n ists .................................................. 14 1.5.1 Phenylethylamines ........................................................................ 15 1.5.2 Conformationally Restricted Analogues of Dopamine 17 1.5.2.1 Miscellaneous Semi-rigid Analogues ................................ 18 1.5.2.2 Aminotetralins ........................................................................ 20 1.5.2.3 Aminoindanes ........................................................................ 22 1.5.2.4 Benzoquinolines ................................................................... 24 1.5.2.5 Nitrogen Heterocycles ......................................................... 25 1.5.3 Naturally Occurring Dopamine A gonists ................................... 26 1.5.3.1 A p o rp h in e s ............................................................................. 27 1.5.3.2 Ergot Alkaloids ...................................................................... 28 vii 1.5.4 Dopamine Bioisosteres ............................................................... 29 1.5.4.1 Permanently Charged Derivatives ..................................... 30 1.5.4.2 Permanently Uncharged Derivatives ................................ 32 1.6 Drug-Receptor Interactions ................................................................... 33 1.6.1 Hydrogen Bonding ........................................................................ 33 1.6.2 Ionic Bonding .................................................................................. 34 1.6.3 Reinforced Ionic Bonding ............................................................ 34 1.7 Summary ................................................................................................... 35 CHAPTER II STATEMENT OF THE PROBLEM AND OBJECTIVES ........................... 37 CHAPTER III RESULTS AND
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