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Proquest Dissertations New paradigm for drug design: Design and synthesis of novel biologically active peptides that are agonists at opioid receptors and antagonists at cholecystokinin receptors Item Type text; Dissertation-Reproduction (electronic) Authors Agnes, Richard S Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 29/09/2021 20:04:47 Link to Item http://hdl.handle.net/10150/280340 NEW PARADIGM FOR DRUG DESIGN: DESIGN AND SYNTHESIS OF NOVEL BIOLOGICALLY ACTIVE PEPTIDES THAT ARE AGONISTS AT OPIOID RECEPTORS AND ANTAGONISTS AT CHOLECYSTOKININ RECEPTORS by Richard Sario Agnes Copyright © Richard Sario Agnes 2003 A Dissertation Submitted to the Faculty of the DEPARTMENT OF CHEMISTRY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2003 UMI Number: 3106966 Copyright 2003 by Agnes, Richard Sario All rights reserved. UMI UMI Microform 3106966 Copyright 2004 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 9 THE UNIVERSITY OF ARIZONA ® GRADUATE COLLEGE As members of the Final Examination Committee, we certify that we have read the dissertation prepared by Sario Agnes entitled NEW PARADIGM FOR DRUG DESIGN: DESIGN AND SYNTHESIS OF NOVEL BIOLOGICALLY ACTIVE PEPTIDES THAT ARE AGONISTS AT OPIOID RECEPTORS AND ANTAGONISTS AT CHOLECYSTOKININ RECEPTORS and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy Victor J Date F-- Robert R. Bates Date Rich^d S. Glass Date Vicki U,ysQ«rki ^ Date/ I S. Scott Saavedra Date ^ Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requireme Disserta®Lon Director ^ictor J. Hruby Date 3 STATEMENT BY THE AUTHOR The dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University library to be made available to borrowers under rules of the library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgement of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the copyright holder. SIGNED: 4 ACKNOWLEDGEMENTS A PhD research project would be very difficult to complete without the kind help of many individuals. I would like to address my appreciation to some of the people without whom this dissertation would never have been possible. I would like to thank Dr. Victor J. Hruby, my research advisor, for his encouragement, friendship, support, understanding, and mentorship throughout the years. Special thanks for the members of my dissertation committee. Dr. Richard Glass, Dr. Robert B. Bates, Dr. Scott Saavedra, Dr. Vicki Wysocki, and the late Dr. David F. O'Brien, for their scientific expertise, encouragement, and support. I would like to thank the core members of the CCK/opioid project, especially to Dr. Frank Porreca and Dr. Josephine Lai, whose insight and vision, along with Dr. Hruby, made this project possible. Thanks to Dr. Yeon Sun Lee and Dr. Balaz Hargaittai for all the discussions and help. Thanks to Peg Davis, Dr. Shou Wu Ma, and Dr. Todd Vanderah for performing the biological assays. Benjamin A. Fish is greatly appreciated for his peptide synthesis work. I would like to express my gratitude to all the members of the Hruby group, Paolo Greico, Andrew Burritt, Preeti Balse, Josue-Alfaro Lopez, Scott Cowell, Toru Okayama, Guoxia Han, Jung Mo Ahn, Josef Vagner, Xue Jun Tang, Xuyuan Gu, John Ndungu, Isabel Alves, Min Ying Cai, Ruben Vardanyan, Zhanna Zhilina, Jinfa Ying, Katalin Kover, Chiyi Xiong, and Junyi Zhang, for their help, support, and friendship. I would like to thanks to all the fnends I have met during these years and in particular, Matthew Golden, Martina Bowen, Anne Runge, Jeimet Lee, Eric Ross, Lisa, Domenic Tiani and Matt Lynn, for their support, encouragement, and friendship. Special thanks to Cheryl McKinley and Margie Colie for their help, support and encouragements. I would to thank Arpad Somogyi and the facility staff for performing the mass spectrometry analysis and Wallace Clark for performing the amino acid analysis. This research was supported by NIDA Grant DA 12394. Thanks to Pfizer Global Research and Development for a 2002 Organic Chemistry Diversity Fellowship. DEDICATION To my mother Maximina Sario Agnes To my father Ricarte A. Agnes To my brother and sister Gilbert Agnes and Joanne Agnes To my grandmother Juana Agnes For all their encouragements, support, and prayers 6 TABLE OF CONTENTS Page ACKNOWLEDGEMENTS 4 LIST OF FIGURES 13 LIST OF TABLES 15 ABSTRACT 18 CHAPTER 1. INTRODUCTION 19 1.1 New paradigm in drug discovery 19 1.2 Neuropathic pain and roles of CCK and opioid systems 23 1.3 Design concepts for agonists and antagonists 24 1.4 Structure-activity relationships of opioid agonists 30 1.4.1 Importance of N-terminal Tyr at position 1 30 1.4.2 Importance of D-amino acids at position 2 31 1.4.3 Importance of the aromatic residues at position 4 31 1.4.4 Substitution at position 5 32 1.4.5 Cyclic analogues of enkephalin 33 1.5 Structure-activity relationships of cholecystokinin 33 1.5.1. Substitutions for Met residues at positions 28 and 31 35 1.5.2 Modifications of Trp residue 36 1.5.3 Cyclic analogues of CCK 36 1.5.4 Structure activity of non-peptide cholecystokinin antagonists 37 7 TABLE OF CONTENTS—CONTINUED 1.6 Overlapping pharmacophores of opioids and cholecystokinin 38 1.7 Rationale for a single molecule targeting multiple receptors 40 1.8 Goals 41 CHAPTER 2. DESIGN, SYNTHESIS, AND STRUCTURE-ACTIVITY RELATIONSHIPS OF CCK/OPIOID PEPTIDES: MODIFICATIONS OF THE LINEAR SEQUENCE 42 2.1 Results: design of linear peptides 42 2.2 Results and discussion: synthesis of linear analogues of CCK/opioid peptides 46 2.2.1 General methods 46 2.2.2 Results: Coupling of Trp"^ and N-MeNle^ 46 2.2.3 Results: Cleavage of linear peptides from the solid support 49 2.2.4 Results: Incomplete deprotection of Trp 50 2.3 Results: Structure-activity relationships of linear CCK/opioid analogues at CCK and opioid receptors 51 2.3.1 Truncation of A^-terminal Asp 52 2.3.2 Substitution at position 2 60 2.3.3 Substitution with Nle^ 61 2.3.4 Substitution with D-Trp"^ 63 2.3.5 Double substitution with D-Trp"* and Nle^ 65 8 TABLE OF CONTENTS—CONTINUED 2.4 Discussions 66 2.4.1 Assessment of the binding affinity and functional assays 66 2.4.2 RSA504 is the most potent analogue of CCK at CCK-A receptors 67 2.4.3 SAR along the peptide backbone at positions 4 and 5 68 2.4.4 Role of D-amino acids at position 2 69 2.4.5 Similarities in opioid and CCK SAR supports the overlapping pharmacophore hj^othesis 70 2.5 Conclusions 71 2.6 Experimental Section 73 2.6.1 Abbreviations 73 2.6.2 Materials 73 2.6.3 General methods for peptide synthesis 75 2.6.4 Purification 77 CHAPTER 3. DESIGN, SYNTHESIS, AND STRUCTURE-ACTIVITY RELATIONSHIPS OF CCK/OPIOID PEPTIDES: SUBSTITUTION OF BULKY RESIDUES 79 3.1 Results: Design ofpeptides with substitution of bulky residues 79 3.2 Results: Structure-activity relationships 84 3.2.1 Substitution of Nal residues at position 4 91 9 TABLE OF CONTENTS—CONTINUED 3.2.2 Substitution of 5'-phenyltryptophan at position 4 93 3.2.3 Substitution of dihydrotryptophan at position 4 94 3.2.4 Substitution of D-homophenylalanine at position 2 96 3.3 Discussions 97 3.4 Conclusions 99 CHAPTER 4. DESIGN, SYNTHESIS, AND STRUCTURE-ACTIVITY RELATIONSHIPS OF CCK/OPIOID PEPTIDES: CYCLIC DISULFIDE ANALOGUES 100 4.1 Results: Design of cyclic disulfide analogues of CCK/opioid peptide.. 100 4.2 Results and Discussion: Synthesis of the cyclic disulfide analogues of CCK/opioid peptide ligands 106 4.3 Results: Structure-activity relationships of the cyclic disulfide analogues Ill 4.4 Discussions 121 4.4.1 Assays 121 4.4.2 Comparison of cyclic disulfide CCK/opioid peptide analogues to opioid ligands 122 4.4.3 Substitution with D-Trp in cyclic disulfide CCK/opioid peptide analogues 123 4.5 Conclusions 124 10 TABLE OF CONTENTS—CONTINUED 4.6 Experimental Section 125 4.6.1 General method for the synthesis of linear peptides for solution phase cyclization 125 4.6.2 General method for potassium ferricyanide disulfide cyclization 125 4.6.3 General method for air oxidation in disulfide cyclization 126 4.6.4 General method for DMSO assisted air oxidation in disulfide cyclization 127 4.6.5 General methods for cyclic disulfide synthesis using on-resin cyclization 127 CHAPTER 5. DESIGN, SYNTHESIS, AND STRUCTURE- ACTIVITY RELATIONSHIPS OF CCK/OPIOID PEPTIDES: LACTAM ANALOGUES 133 5.1 Results: Design of lactam analogues 133 5.2 Results: Synthesis of lactam analogues 137 5.3 Results: Structure-activity relationships 143 5.4 Discussions 154 5.4.1 Assessment of the bioassays 155 5.4.2 Role of position 2 in CCK-antagonist properties 156 5.4.3 Comparison to opioid ligands 157 11 TABLE OF CONTENTS—CONTINUED 5.4.4 Differential opioid agonist and CCK antagonist activities 158 5.4.5 Comparison of cyclic lactam to cyclic disulfide 159 5.4.6 Compatibility of D-Trp with non-methylated residue at position 5 in cyclic lactam 160 5.5 Conclusions 161 5.6 Experimental section 162 5.6.1 Abbreviations 162 5.6.2 Materials 162 5.6.3 General method for peptide synthesis 164 5.6.4 General method for cyclization via lactam bridge 166 5.6.5 Purification 167 CHAPTER 6.
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