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Information to Users INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. U M I 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 U M I a complete manuscript and there are missing pages, these w ill 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 U M I 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 9427799 Part 1: Design, synthesis and biological activities2-(4 of -isothiocyanatobenzyl)imidazoline analogues in rat and bovine tissues. Part 2: Design and synthesis of selective 2-amino-3-(3 -hydroxy-5f -methylisoxazol-4 t -yl)propanoic acid (AMPA) receptor antagonists for potential use in drug abuse Slavica, Meri, Ph.D. The Ohio State University, 1994 Copyright ©1994 by Slavica, Meri. All rights reserved. UMI 300 N. Zeeb Rd. Ann Arbor, MI 48106 Part 1: Design, Synthesis and Biological Activities of 2-(4’-lsothiocyanatobenzyl)imidazoline Analogues in Rat and Bovine Tissues Part 2: Design and Synthesis of Selective 2-Amino-3-(3’-hydroxy 5’-methylisoxazol-4’-yl)propanoic Acid (AMPA) Receptor Antagonists for Potential Use in Drug Abuse DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University by Meri Slavica, B.S. Pharm. ***** The Ohio State University 1994 Dissertation Committee: 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. Brueggemei&^Ph.D., co-advisor College of Pharmacy Copyright by Meri Slavica 1994 DEDICATION To my Mom and Dad & ACKNOWLEDGEMENTS I would like to express my sincere thanks to the following individuals: Dr. Duane D. Miller for his guidance, friendship and never ending enthusiasm throughout my graduate career, and especially for his encouragement and support after moving to UT-Memphis. The members of my dissertation committee Dr. Robert Brueggemeier, Dr. Dennis Feller and Dr. Larry Robertson for their help and advice in preparing this manuscript. Longping Lei (M.S.), Dr. Popat Patil and Dr. Dennis Feller (fax-pals) for their patience and persistence in obtaining the pharmacological data for IBI analogues in rat aortic tissues. Also for their good sense of humor that was a necessity in a process of solving the IBI mystery. Dr. Norman Uretsky, Dr. Lane Wallace and Ms. Kara Brooks for their work on the biological evaluation of the AMPA antagonists. Dr. Norman Uretsky for his comments and help in preparing the second part of this document. Dr. Paul Ernsberger for the pharmacological data of IBI and its analogues in the bovine ventrolateralmedulla. Dr. Jeff Herndon for his invaluable help and advice on molecular modeling aspects of this work and for his friendship. John Miller for his help in running the NMR (specially one at the College of Pharmacy, UT Memphis), obtaining mass spectra of my compounds and for his support and friendship. Ms. Kathy Brooks for all her help and assistance with administrative problems, for securing my paychecks and specially for helping me meet the graduation requirements and deadlines. Ms. Stella Bain (UT-Memphis), Ms. John Dandrea (OSU) and Ms. Carol Settlers for all their help and assistance throughout my stay at The Ohio State University and University of Tennessee-Memphis. The faculty members of the Division of Medicinal Chemistry and Pharmacology at The Ohio State University: Dr. Robert Brueggemeier, Dr. Robert Curley, Dr. Raymond Doskotch, Dr. Duane Miller, Dr. Carter Olson, Dr. Larry Robertson, Dr. Albert Soloway and Dr. Donald Witiak for giving me an opportunity to study in the USA, for sharing their, knowledge, and for providing me with excellent environment to learn and work. I would also like to take this opportunity and thank them for awarding me with Hoechst-Roussel Graduate Student Award in Medicinal Chemistry. My friends and lab-mates: Kim, Hong, Mustapha, Yasser, Kazu, Yoshiya, Ron, Jeff, Pat, Sun, Joe, Pam, Lakshmni and Sophie for their friendship, advice, help, support and tolerance. The Ohio State University and National Institute of Health for their financial support. Most of all to John H. Sheley for his love, friendship, support and tolerance. Teddy Bear, I wouldn’t be able to make it without you! VITA June 1,1965 Bom-Sibemk, Croatia (Yugoslavia) Jun, 1987 B.S. Pharmacy, College of Pharmacy, University of Zagreb Zagreb, Croatia(Yugoslavia) Jan. 1 9 8 8 -Sept. 1989 Graduate Teaching Assistant College of Pharmacy University of Zagreb Zagreb, Croatia(Yugoslavia) Sept. 1989-July 1991 Graduate Teaching Assistant College of Pharmacy, The Ohio State University Columbus, Ohio July 1991 - Oct. 1992 Graduate Research Associate College of Pharmacy, The Ohio State University Columbus, Ohio Oct. 1992-present Graduate Research Associate College of Pharmacy, University of Tennessee-Memphis PUBLICATIONS 1. Rendic, S.; Slavica, M. Urinary Excretion and Metabolism of Orally Administered Mefenorex. In Recent Advances in Doping Ana/ys/s-Proceedings of the 11th Cologne Workshop on Dope Analysis 7th-12th March 1993. Eds. M. Donike, H. Geyer, A. Gotzmann, U. Mareck-Engelke, S. Rauth, Sport und Buch Strau(3, Koeln 1994. 2. Rendic, S.; Slavica, M. Urinary Excretion and Metabolism of Orally Administered Mefenorex. Eur. J. Drug Metab. Pharmacokin. (accepted for publication) 3. Slavica, M.; Lei, L.; Patil, P.; Kerezy, A.; Feller, D.; Miler, D. Synthesis and Biological Activities of a New Set of Irreversibly Acting 2-(4’-lsothiocyanatobenzyl)imidazoline (IBI) Analogues in Rat Thoracic Aorta. J. Med. Chem. (in press) FIELDS OF STUDY Major Reid: Pharmacy Studies in Synthetic Medicinal Chemistry v TABLE OF CONTENTS PAGE DEDICATION .................................................................................................... i ACKNOWLEDGEMENTS ..................................................................................... iii VITA ........................................................................................................................ v LIST OF FIGURES................................................................................................. Ix LIST OF TABLES................................................................................................... xii LIST OF SCHEMES.................................................................................................xiv Part 1 Design, Synthesis and Biological Activities of 2-(4’-lsothiocyanatobenzyl) imidazoline Analogues in Rat andBovine Tissues .............................................. 1 CHAPTER I INTRODUCTION ............................................ 2 1.1 The Autonomic Nervous System .................................................................. 2 1.2 The Adrenergic Nervous System .................................................................. 3 1.2.1 Subclassification of a-Adrenergic Receptors ......................................... 4 1.2.2 Subclassification of a-i-and ar Adrenergic Receptors ........................... 7 1.2.3 Molecular Biology of a-Adrenergic Receptors ....................................... 10 1.2.3.1 Purification, Cloning and Expression of ar AR — .................... 10 1.2.3.2 Purification, Cloning and Expression of 0 2 -AR ............................. 11 1.2.4 a-Adrenergic Receptor Structure .......................................................... 13 1.2.5 The Role of Affinity and Photoaffinity Labeling Techniques and Site Directed Mutagenesis in Molecular Characterization of a-AR .................. 16 1.2.6 a-Adrenergic Receptors and their Signal Transduction Pathways 18 1.3 Calcium Channels ......................................................................................... 20 1.3.1 Classification of Calcium Channels ...................................................... 21 1.3.2 Drugs Active at Calcium Channels ........................................................ 23 1.3.2.1 Calcium Channel Antagonists ...................................................... 23 1.3.2.2 Calcium Channel Agonists(activators) ......................................... 27 1.3.3 Structure of the Calcium Channels ......................................................... 28 1.3.4 The Role of Affinity and Photoaffinity Labeling in the Identification of Calcium Channel Antagonist Binding S ites ........................................... 30 1.4 Imidazoline Receptors ..................................................................................
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