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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 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 C om pany 300 North Z eeb Road. Ann Arbor. Ml 48106-1346 USA 313/761-4700 800 521-0600 Order Number 9120692 Part 1. Synthesis of fiuorinated catecholamine derivatives as potential adrenergic stimulants and thromboxane A 2 antagonists. Part 2. Synthesis of hydrazinium analogs of dopamine agonists and antagonists Markovich, Kimberly M., Ph.D. The Ohio State University, 1991 Copyright ©1991 by Markovich, Kimberly M. All rights reserved. UMI 300 N. Zeeb Rd. Ann Arbor, MI 48106 NOTE TO USERS THE ORIGINAL DOCUMENT RECEIVED BY U.M.I. CONTAINED PAGES WITH SLANTED PRINT. PAGES WERE FILMED AS RECEIVED. THIS REPRODUCTION IS THE BEST AVAILABLE COPY. Part 1: Synthesis of Fluorinated Catecholamine Derivatives as Potential Adrenergic Stimulants and Thromboxane A2 Antagonists Part 2: Synthesis of Hydrazinium Analogs of Dopamine Agonists and Antagonists DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Kimberly M. Markovich, B.S., R.Ph. * * it * * The Ohio State University 1991 Dissertation Committee: Approved by Duane D. Miller, Ph.D. Robert W. Brueggemeier, Ph.D. Dennis R. Feller, Ph.D. Donald T. Witiak, Ph.D. Duane D. Miller, Ph.D., Advisor College of Pharmacy Copyright by Kimberly M. Markovich 1991 DEDICATION To Steve - ii - ACKNOWLEDGEMENTS I would like to express my sincere thanks to the following individuals: Dr. Duane D. Miller, for his guidance, support and friendship throughout my graduate career. The members of my reading committee, Dr. Robert Brueggemeier, Dr. Dennis Feller and Dr. Donald Witiak, for their advice in the preparation of this manuscript. Dr. Yoshiya Amemiya, for his invaluable advice on both chemistry technique and various synthetic aspects of this work and his friendship. Dr. Akihiko Hamada, for his much appreciated advice with various aspects of this work and for synthesizing the racemic dibenzyloxy protected 8 -fluorotrimetoquinol. Dr. Karl Romstedt, Dr. Gamal Shams, Katherine Doyle, Paul Fraundorfer and Dr. Dennis Feller, for the pharmacological data of the trimetoquinol derivatives and their help in the interpretations of the data. Tahira Farooqui and Dr. Norman Uretsky, for their work on the biological studies of the dopamine antagonists. Jack Fowble for his help in obtaining and interpreting various spectra, for sharing his pearls of wisdom and his friendship. John Miller, for running my mass spectra on demand, for his help in obtaining other various spectra and for his support and friendship. My fellow graduate students, especially Vimon Tantishaiyakul, Mustapha Beleh, Soheila Ebrahimian and Allen Hopper for their friendship, advice, and for their never ending support (and sarcasm). Bruce Posey, for assistance in using the college computer system, especially for the preparation of this document. - iii - Dr. Kurt Loening, for his assistance with the nomenclature of the hydrazinium analogs. Carol Settles, for her friendship and continued support throughout my graduate career. Most of all, to Dr. Stephen Beck-thanks for waiting. - iv - VITA June 9, 1963 Dorn - Chicago, Illinois May, 1986 B.S. Pharmacy, Butler University, Indianapolis, Indiana 1986-present Academic Challenge Fellow The Ohio State University Columbus, Ohio Sept. 1986 - Aug. 1988 Graduate Teaching Assistant College of Pharmacy The Ohio State University Sept. 1988 - present Graduate Research Associate College of Pharmacy The Ohio State University PUBLICATIONS 1. Gary L. Grunewald, Kimberly M. Markovich, and Daniel J. Sail, "Orientation of Amphetamine and Norfenfluramine Analogues in the Benzonorbornene and Benzobicyclo[3.2.1]octane Ring Systems at the Active Site of Phenylethanolamine N-Methyltransferase (PNMT)", J. Med. Chem. 1987, 30, 2191. 2. Kimberly M. Markovich, Akihiko Hamada, and Duane D. Miller, "Unexpected Aminoisoquinoline Formed Under Bischler-Napieralski Conditions Provides For A New Synthesis of 3-Aminoisoquinolines", J. Heterocyclic Chem. 1990, 27, 1665. FIELDS OF STUDY Major Field: Pharmacy Studies in Synthetic Medicinal Chemistry TABLE OF CONTENTS PAGE D e d i c a t i o n ............................................................ ii Acknowledgements ................................................... iii VITA ................................................................. v List of............. F i g u r e s ..........................................vii List of T a b l e s ........................................ viii List of Schemes ...........................................ix CIIAPTER Part 1: Synthesis of Fluorinated Catecholamine Derivatives as Adrenergic Stimulants and Thromboxane Aj Antagonists . 1 INTRODUCTION ........................................................ 2 1.1 Sympathetic Nervous System ................................ 2 1.1.1 Catecholamine Biosynthesis .......................... 3 1.1.2 Storage and Release of Catecholamines ............. 5 1.1.3 Metabolism and Reuptake .............................. 6 1.2 Subclassification and Signal Transduction of Adrenergic Receptors ....................................... 9 1.3 Structural Properties of Adrenergic Receptors ........ 31 1.4 Structure Activity Relationships of Adrenergic R e c e p t o r s .................................................. 38 1.4.1 Alpha Adrenergic Agonist Structure Activity Relationships ....................................... 38 1.4.2 Beta-2 Adrenergic Agonist Structure Activity Relationship ....................................... 47 - vi - 1.5 Physiological Functions of Adrenergic Agonists ......... 50 1 .6 Thromboxane A £ ............................................55 1.6.1 Hemostasis and Platelet Function ................. 57 1 .6.2 Biochemical Role of TXA« in Platelet Activation . 61 1.6.3 TXA2 Involvement in Cardiovascular Disease .... 65 1.6.4 TXA2 Antagonists .....................................66 STATEMENT OF PROBLEMS AND OBJECTIVES ............................. 69 2.1 Trimetoquinol Analogs ................................. 69 2.2 Imidazoline Derivatives ................................ 74 2.3 Norepinephrine Derivatives ............................. 77 RESULTS AND DISCUSSION ........................................... 79 3.1 CHEMISTRY ..................................................79 3.1.1 Synthesis of 5- and 8 -Trifluoromethylated Trimetoquinol Analogs .............................. 79 3.1.2 Separation of 8 -Fluorotrimetoquinol Enantiomers . 97 3.1.3 Trifluoromethylated Catecholimidazoline Analogs . 99 3.1.4 Trifluoromethylated Norepinephrine Analogs .... 103 3.2 B I O L O G Y ...................................................109 3.3 S U M M A R Y ...................................................113 EXPERIMENTAL ..................................................... 115 Part 2: Synthesis of Ilydrazinium Analogs of Dopamine Agonists and Antagonists .................................................160 INTRODUCTION ..................................................... 161 5.1 Location, Distribution and Function of Dopamine .... 161 5.2 Dopamine Receptor Subtypes ............................. 163 STATEMENT OF PROBLEMS AND OBJECTIVES ............................ 171 RESULTS AND DISCUSSION .......................................... 180 7.1 CHEMISTRY ................................................ 180 7.2 BIOLOGY .................................................. 197 7.3 SUMMARY .................................................. 197 EXPERIMENTAL ..................................................... 198 BIBLIOGRAPHY ........................................................ 209 - vii - LIST OF FIGURES Catecholamine biosynthesis .............................. 4 Metabolic pathways of catecholamines ................... 7 fij- and fi 2 _Adrenoceptor agonists and antagonists . 11 Atypical adipocyte-selective beta-adrenoceptor agonists . 12 a^-Adrenoceptor agonists and antagonists................. 14 (^“Adrenoceptor agonists and antagonists................. 15 a 2fi-Adrenoceptor selective compounds ................... 22 Mechanism of signal transduction upon OC^-adrenoceptor stimulation ..............................................
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