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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 prfritar. 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 9211148 Synthesis and biological results of compounds acting on alpha-adrenergic receptors Hong, Seoung Soo, Ph.D. The Ohio State University, 1991 Copyright ©1991 by Hong, Seoung Soo. All rights reserved. UMI 300 N. Zeeb Rd. Ann Arbor, MI 48106 SYNTHESIS AND BIOLOGICAL RESULTS OF COMPOUNDS ACTING ON ALPHA-ADRENERGIC RECEPTORS DISSERTATION Presented in Partial Fulfillment of the Requirement for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Seoung Soo Hong/ B.S., M.S. * * * * ★ The Ohio State University 1991 Dissertation Committee: Approved by Duane D. Miller, Ph.D. Robert W. Brueggemeier, Ph.D. Larry W. Robertson, Ph.D. Dennis R. Feller, Ph.D. Duane D. Miller, Ph.D., Advisor College of Pharmacy Copyright by Seoung Soo Hong 1991 DEDICATION To my parents, wife, children, and family ii ACKNOWLEDGEMENTS I would like to express my sincere thanks to the following individuals: Dr. Duane D. Miller, my adviser, for his guidance, unending encouragement, and understanding throughout my graduate career, making this dissertation possible. Drs. Dennis R. Feller, Karl J. Romstedt, for the pharmacological data and their help in the interpretation of the data. Carol Settles, for her friendship and greately appreciated assistance throughout my graduate career. The falculty, staff and my fellow graduate students, Ron Hill, Kimberly Markovich, Kazu Matsumoto, for their friendship and support during my graduate study, especially Ron for help preparing this manuscript. Drs. C. George, Judy Flippen-Anderson at the Naval Research Laboratory, for their assistance for X-ray analysis. Dr. Fu-Lian Hsu at the U.S. Army Chemical Research, for his invaluable discussion on the synthesis of medetomidine analogs. Jack Fowble and John Miller, for their assistance in obtaining and interpreting the NMR and mass spectra. Financial supports from U.S. Army CRDEC and the National Institute of Health are gratefully acknowledged. iii VITA August 18, 1955 Born - Taegu, Korea 1981 B.S. Pharmacy, Yeungnam University, Taegu, Korea 1984 M.S. Pharmacy, Yeungnam University, Taegu, Korea 1986 - present Graduate Research Associate, College of Pharmacy, The Ohio State University PUBLICATIONS 1. See-Ryun Chung, Seoung-Soo Hong, and Kyung Hee Jeune- Chung, "Isolation and Purification of Lectin from Phaseolus radiatus", Yakhak Hoeji 1983, 2J_, 221. 2. Yoshia Amemiya, Seoung S. Hong, Burrah V. Venkataraman, Popat N. Patil, Gamal Shams, Karl Romstedt, Dennis R. Feller, Fu-Lian Hsu, and Duane D. Miller, "Synthesis and a-Adrenergic Activities of 2- and 4-Substituted Imidazoline and Imidazole Analogs", J. Med. Chem., in press. 3. S.S. Hong, D.D. Miller, K. Matsumoto, K.L. Romstedt and D.R. Feller, "Synthesis, Isolation, Characterization and a2~Adrenergic Activity of the Optical Isomers of 4-[l-(l- Naphthyl)Ethyl]-1H-Imidazole", Proceedings of the 1991 U.S. Army CRDEC, in press. 4. K. Matsumoto, S.S. Hong, K.L. Romstedt, D.R. Feller and D.D. Miller, "a2-Adrenergic Activity of a New Series of Analogs of 4-[l-(1-Naphthyl)Ethyl]-lH-Imidazole", Proceedings of the 1991 U.S. Army CRDEC, in press. FIELDS OF STUDY Major Field: Pharmacy Studies in Synthetic Medicinal Chemistry v TABLE OF CONTENTS PAGE D e d i c a t i o n ............................................... ii Acknowledgements ....................................... iii VITA .................................................... iv List of Fi g u r e s ...................................... viii List of Tables ........................................ x List of Schemes ........................................ xi CHAPTER I INTRODUCTION ...................................... 1 1.1 The Nervous System ......................... 1 1.2 The Adrenergic Neuronal System ............ 3 1.2.1 Biosynthesis of Catecholamines • • • 4 1.2.2 Catecholamine Storage ............. 6 1.2.3 Catecholamine Release ............. 7 1.2.4 Catecholamine Metabolism and Reuptake ...................... 7 1.3 Subclassification of a-Adrenergic R e c e p t o r s .................................. 11 1.4 Signal Transduction of a-Adrenergic R e c e p t o r s .................................. 24 1.5 Structural Properties of a-Adrenergic Receptors ................... 30 1.6 Structure Activity Relationships of a-Adrenergic Agonists ............... 33 1.7 Structure Activity Relationships of a-Adrenergic Antagonists ........... • 45 1.8 Physiological Functions of a-Adrenergic Agonists and Antagonists • • * 49 II STATEMENT OF PROBLEMS AND OBJECTIVES ............ 53 2.1 Medetomidine Analogs .................... 53 2.2 Phentolamine Analogs .................... 61 Ill RESULTS AND DISCUSSION...........................66 3.1 Chemistry .............................. 66 3.1.1 Synthesis of Naphthalene Analogs of Medetomidine.................. 66 3.1.2 Resolution of 4-[1-(1-naphthyl) ethyl]imidazole enantiomers * • • • 75 3.1.3 Synthesis of Indole Analogs of Medetomidine ................... 82 3.1.4 Synthesis of Phentolamine Analogs • 90 3.2 Biology ................................ 99 3.3 Summary ................................. 107 IV EXPERIMENTAL.................................. 109 BIBLIOGRAPHY ............................................ 154 vii LIST OF FIGURES FIGURE PAGE 1. Subdivision of the nervous system .................. 2 2. Biosynthesis of catecholamines.................... 5 3. Norepinephrine and epinephrine metabolism .......... 9 4. The formation of an aldehyde by M A O ................. 10 5. c^-Adrenoceptor agonists and antagonists .......... 13 6. a2-Adrenoceptor agonists and antagonists.......... 14 7. a2B~Adrenergic receptor selective compounds ........ 22 8. Modern classification of adrenoceptors ............ 24 9. Signal transduction mechanism activated by a^-adrenoceptor ..................................... 26 10. G protein coupled signal transduction .............. 29 11. Signal transduction mechanism activated by presynaptic a2-adrenoceptors ...................... 29 12. Topography of the human a2ft-adrenergic receptor • • • 31 13. Proposed conformation of norepinephrine and clonidine for interaction with a-adrenergic receptors ........................ 35 14. Schematic representation of the Easson-Stedman hypos i s ...............................................36 15. Aromatic ring substituted clonidine-like compounds • 42 16. Imidazoline modified clonidine-like compounds • • • • 44 17. Prazosin derivatives as c^-adrenergic antagonists .......................................... 45 viii 18. Angles between naphthalene, indole rings and a carbon bridge containing imidazole r i n g .................................... 56 19. HPLC chromatogram for the racemic mixture of 4-[1-(1-naphthyl)ethyl]imidazole ............... 79 20. HPLC chromatograms for each enantimer of 4-[l-(1-naphthyl)ethyl]imidazole ................. 80 21. ORTEP representation of (S)-4-[l-(1-naphthyl) ethyl]imidazole .................................... 81 22. Resonance hybrids of indole ....................... 82 23. ORTEP representation of Z-102 ...................... 98. ix LIST OF TABLES TABLE PAGE 1. c^-Adrenergic Receptor Subtype Characteristics • • • 20 2. Differences between Phenethylamines and Imidazolines for Agonist Activity ............... 34 3. Physiological Functions of a-Adrenoceptors ........ 52 4. c^/c^-Selectivity of Medetomidine and its Optical Isomers with Reference Compounds in Rat Brain Membranes ............................. 55 5. Comparison of Medetomidine and its Optical Isomers with Reference Compounds in Mouse vas deferens ............................. 58 6. Functional Groups used as Isosteric Replacements* • 63 7. Comparison of Adrenergic Activities of Medetomidine (51) and Analog S4 in Rat Aorta and Human Platelets .....................100 8. Inhibition of Epinephrine-Induced Human Platelet Aggregation by Compounds j54, S(+)-52, and R( -) -57 • 102 9. Comparison of Adrenergic Activities of Compounds 54, R(-)-57, S(+)-57, and Reference Compounds .............................. 103 10. Inhibition of Epinephrine-Induced Human Platelet