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Peptide, Peptidomimetic and Small Molecule Based Ligands Targeting Melanocortin Receptor System

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Peptide, Peptidomimetic and Small Molecule Based Ligands Targeting Melanocortin Receptor System PEPTIDE, PEPTIDOMIMETIC AND SMALL MOLECULE BASED LIGANDS TARGETING MELANOCORTIN RECEPTOR SYSTEM By ALEKSANDAR TODOROVIC A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2006 Copyright 2006 by Aleksandar Todorovic This document is dedicated to my family for everlasting support and selfless encouragement. ACKNOWLEDGMENTS I would like to thank and sincerely express my appreciation to all members, former and past, of Haskell-Luevano research group. First of all, I would like to express my greatest satisfaction by working with my mentor, Dr. Carrie Haskell-Luevano, whose guidance, expertise and dedication to research helped me reaching the point where I will continue the science path. Secondly, I would like to thank Dr. Ryan Holder who has taught me the principles of solid phase synthesis and initial strategies for the compounds design. I would like to thank Mr. Jim Rocca for the help and all necessary theoretical background required to perform proton 1-D NMR. In addition, I would like to thank Dr. Zalfa Abdel-Malek from the University of Cincinnati for the collaboration on the tyrosinase study project. Also, I would like to thank the American Heart Association for the Predoctoral fellowship that supported my research from 2004-2006. The special dedication and thankfulness go to my fellow graduate students within the lab and the department. iv TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................................................................................. iv LIST OF TABLES........................................................................................................... viii LIST OF FIGURES .............................................................................................................x ABSTRACT..................................................................................................................... xiv CHAPTER 1. INTRODUCTION ........................................................................................................1 Melanocortin System and Physiological Implications .................................................1 Melanocortin Receptors................................................................................................5 Naturally Processed Melanocortin Agonists ................................................................8 Endogenous Melanocortin Receptor Antagonists ......................................................12 The Contribution of Research in This Dissertation to the Melanocortin System.......14 2. GENERAL METODOLOGIES.................................................................................16 Solid Phase Peptide Synthesis (SPPS)........................................................................16 Fmoc Solid Phase Peptide Synthesis...................................................................20 Advantages, Disadvantages and Chemistry Beyond the Fmoc SPPS .................23 Synthesis Initiation and Subsequent Deprotection.......................................24 Coupling Methods........................................................................................27 Colorimetric Qualitative Tests and Analytical Characterization .................33 3. N-FATTY ACYLATED MELANOCORTIN TETRAPEPTIDES: INFLUENCE OF THE FATTY ACID CHAIN LENGTH ON AGONIST POTENCY AND SELECTIVITY AT THE MOUSE MELANOCORTIN RECEPTORS AND TYROSINASE ACTIVITY AT HUMAN MELANOCYTES ..................................37 Introduction.................................................................................................................37 Results.........................................................................................................................39 Chemical Synthesis and Characterization. ..........................................................39 In Vitro Pharmacology at the Mouse Melanocortin Receptors...........................40 Discussion...................................................................................................................42 MCR Agonist Activity and the LCFA Length ....................................................44 v MCR Selectivity and the LCFA Length..............................................................48 Melanocyte Tyrosinase Activity..........................................................................50 Prolongation Effect..............................................................................................52 Summary.....................................................................................................................55 4. DOUBLE SIMULTANEOUS SUBSTITUTION: A STRATEGY IN THE DESIGN, SYNTHESIS AND IN VITRO CHARACTERIZATION OF NOVEL MELANOCORTIN LIGANDS BASED ON A TETRAPEPTIDE TEMPLATE .....57 Introduction.................................................................................................................57 Results.........................................................................................................................62 Chemical Synthesis and Characterization ...........................................................62 Biological Characterization.................................................................................65 Pharmacology at the mMC1R ......................................................................65 Pharmacology at the mMC3R ......................................................................69 Pharmacology at the mMC4R ......................................................................73 Pharmacology at the mMC5R ......................................................................74 Discussion...................................................................................................................76 Simultaneous Double Substitutions at the N-Terminus “Capping Region” and 1 2 3- 4 Position 1 or 2 or 4 in the Ac-His -Dphe -Arg Trp -NH2 Tetrapeptide Template. .........................................................................................................78 Simultaneous Double Substitutions at Positions 1 and 2 in the Ac-His1- 2 3 4 DPhe -Arg -Trp -NH2 Tetrapeptide Template ................................................81 Simultaneous Double Substitutions at Positions 1 and 4 in the Ac-His1- 2 3 4 DPhe -Arg -Trp -NH2 Tetrapeptide Template. ...............................................83 Simultaneous Double Substitutions at Positions 2 and 4 in The Ac-His1- 2 3 4 Dphe -Arg -Trp -NH2 Tetrapeptide Template. ...............................................86 Conclusion ..................................................................................................................87 5. SYNTHESIS AND ACTIVITY OF THE MELANOCORTIN TETRAPEPTIDES WITH AMIDE BOND MODIFICATIONS...............................................................89 Introduction.................................................................................................................89 Results.........................................................................................................................91 Discussion...................................................................................................................95 Synthesis..............................................................................................................95 Activity................................................................................................................99 Conclusion ................................................................................................................102 6. MELANOCORTIN LIGANDS BASED ON THE BENZIMIDAZOLE SCAFFOLD..............................................................................................................104 Introduction...............................................................................................................104 Combinatorial Chemistry and Drug Design......................................................104 Privileged Structure Concept.............................................................................106 Results.......................................................................................................................107 Chemical Synthesis and Characterization .........................................................107 vi Biological Results..............................................................................................107 Discussion.................................................................................................................114 Conclusions...............................................................................................................122 7. EXPERIMENTAL....................................................................................................123 Peptide Synthesis......................................................................................................123 Long Chain Fatty Acylated Melanocortin Tetrapeptides ..................................123 Double Simultaneously Substituted (DSS) Melanocortin Tetrapeptides ..........125 Peptidomimetics Synthesis .......................................................................................129 N-Alkylated and Peralkylated Melanocortin Tetrapeptides..............................129 The Reduction of Phe-DPhe-Arg-Trp-NH2 Peptide into the Polyamine...........132 Synthesis of Benzimidazoles on Solid Support........................................................134
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