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Synthesis of Selective 5-HT7 Receptor Antagonists Georgia State University ScholarWorks @ Georgia State University Chemistry Theses Department of Chemistry Fall 11-18-2011 Synthesis of Selective 5-HT7 Receptor Antagonists Adam Ehalt Georgia State University, [email protected] Follow this and additional works at: https://scholarworks.gsu.edu/chemistry_theses Recommended Citation Ehalt, Adam, "Synthesis of Selective 5-HT7 Receptor Antagonists." Thesis, Georgia State University, 2011. https://scholarworks.gsu.edu/chemistry_theses/45 This Thesis is brought to you for free and open access by the Department of Chemistry at ScholarWorks @ Georgia State University. It has been accepted for inclusion in Chemistry Theses by an authorized administrator of ScholarWorks @ Georgia State University. For more information, please contact [email protected]. SYNTHESIS OF SELECTIVE 5-HT7 RECEPTOR ANTAGONISTS by ADAM J. EHALT Under the Direction of Dr. Lucjan Strekowski ABSTRACT The 5-HT7 receptor is the most recent addition to the 5-HT receptor family and has been linked to a variety of physiological and pathophysiological processes. Well established antide- pressant pharmaceuticals have recently been found to activate the 5-HT7 receptor, supporting the role of the 5-HT7 receptor in the antidepressant mechanism. The synthesis of potent selec- tive 5-HT7 receptor antagonists could afford a greater understanding of the 5-HT7 receptor function as well as lead to potential drug candidates. The synthesis of unfused biheteroaryl derivatives as 5-HT7 receptor ligands has been de- scribed within. These compounds have been tested for biological activity on the 5-HT6 and 5- HT7 receptors. 4-(3’-Furyl)-2-(N-substituted-piperazino)pyrimidines were found to be potent 5- HT7 receptor ligands. 4-(2’-Furyl)-2-(N-substituted-piperazino)pyrimidines have shown high se- lectivity for the 5-HT7 receptor over the 5-HT6 receptor. INDEX WORDS: Serotonin, 5-HT7 receptor, Organic, Heterocyclic chemistry, Synthesis, Pyrimi- dine, Piperazine, Biheteroaryl SYNTHESIS OF SELECTIVE 5-HT7 RECEPTOR ANTAGONISTS by ADAM J. EHALT A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Masters of Science in the College of Arts and Sciences Georgia State University 2011 Copyright by Adam Jay Ehalt 2011 SYNTHESIS OF SELECTIVE 5-HT7 RECEPTOR ANTAGONISTS by ADAM J. EHALT Committee Chair: Dr. Lucjan Strekowski Committee: Yujun Zheng Markus Germann Electronic Version Approved: Office of Graduate Studies College of Arts and Sciences Georgia State University December 2011 iv ACKNOWLEDGEMENTS I would like to thank Dr. Strekowski for allowing me to work independently in his labora- tory and for helping me develop my skills as a synthetic chemist. I would also like to thank Nilmi Fernando and Shirish Paranjpe for their help and support in the lab, for both work and non- work related issues. To my fellow 688 Kell Hall researchers, Reid Daniel, Beth Raux, Jamie Gragg, Ava Blake and Jeff Klenc, you all made working in this lab an incredible and unforgetta- ble experience. I would also like to thank my parents, Jay and Becky Ehalt, for their continued support of my endeavors. Without their encouragement this achievement would not have been possible. v TABLE OF CONTENTS ACKNOWLEDGEMENTS ................................................................................................................................ iv LIST OF TABLES ............................................................................................................................................ vii LIST OF FIGURES ..........................................................................................................................................viii 1 INTRODUCTION (LITERATURE REVIEW) .................................................................................... 1 1.1 Discovery of Serotonin .......................................................................................... 2 1.2 The 5-HT Receptor................................................................................................. 4 1.3 Discovery of the 5-HT7 Receptor ........................................................................... 5 1.4 5-HT7 Receptor Function ..................................................................................... 10 2 SYNTHESIS OF UNFUSED BIHETEROARYLS (THIS WORK) ........................................................ 11 2.1 Synthesis of Substituted Pyrimidines .................................................................. 11 3 BIOLOGICAL ACTIVITY .............................................................................................................. 15 3.1 5-HT7 and 5-HT6 Receptor Binding Affinity ......................................................... 15 4 CONCLUSION ........................................................................................................................... 20 5 EXPERIMENTAL ........................................................................................................................ 21 5.1 General ................................................................................................................ 21 5.2 Lithium Reagents ................................................................................................. 22 5.3 Synthesis of Pyrimidines ..................................................................................... 22 5.4 Hydrobromic Salt Preparation ............................................................................ 24 5.5 Compound Characterization ............................................................................... 24 vi 6 REFERENCES ............................................................................................................................ 27 7 SPECTRA .................................................................................................................................. 30 vii LIST OF TABLES Table 1.1: Binding Affinity Results for 4-(2’Furyl) and 4-(3’-Furyl) pyrimidine derivatives…..…….16 Table 1.2: Binding Affinity Results for Di- and Tri- Substituted Pyrimidines……………..……………….18 viii LIST OF FIGURES Figure 1. 5-Hydroxytryptamine (5-HT, Serotonin)…………………………….….……….…….…….…..1 Figure 2. Lysergic Diethyl Amide (LSD-25, LSD)…………………………………………….…...…..………4 Figure 3. 8-hydroxy-2(di-n-propylamino)-tetralin (8-OH DPAT)……………………….…….……...6 Figure 4. Selective and Non-Selective 5-HT7 Receptor Ligands……….……………….……..……..7 Figure 5. Pharmacophore Model for Selective 5-HT7 Antagonists………………….……….….….9 Figure 6. Cis- and trans- 4-(2’-Furyl) and 4-(3’-Furyl)pyrimidine conformations……...……19 1 1 INTRODUCTION (LITERATURE REVIEW) Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter responsible for a variety of biological functions in animals.1 In humans, the effects of 5-HT are achieved through interac- 1 tions with seven different serotonin receptor families, 5-HT1-7. NH2 HO N H Figure 1. 5-Hydroxytryptamine (5-HT, Serotonin) In the central nervous system (CNS), many processes are directed by serotonin such as feeding, mood, cognition and memory.1,2 In the peripheral nervous system (PNS), serotonin re- gulates cardiovascular and gastrointestinal functioning, smooth muscle contractions, and plate- let aggregation.1,2 Given the many processes governed by serotonin, 5-HT receptors have prov- en to be successful medicinal targets for the treatment of many physiological disorders.2,6 Many current therapeutic agents disrupt or modulate activity of 5-HT receptors through various chemical interactions.2 Each of the seven 5-HT receptor families fills a specific role in achieving the physiological and pathophysiological functions regulated by serotonin.2,6 Synthesis of a 5-HT ligand with receptor family selectivity could afford more specific and efficient treatment and consequently minimize drug side effects. Pursuit of a potent ligand that expresses selectivity for a specific 5-HT receptor family would not be modeled after 5-HT because the native ligand 5-HT is inherently non-selective. The molecule must maintain the 5-HT receptor binding pocket specifications but must be chem- 2 ically distinct to avoid unwanted biological interactions. The 5-HT7 receptor is the most recently discovered 5-HT receptor and it has generated the interest of medicinal chemists as a potential therapeutic target for the treatment of clinical depression.6 The development of more potent and selective 5-HT7 receptor ligands is driven by the potential for the future medicinal applica- tions. 1.1 Discovery of Serotonin 5-HT was discovered independently by two American research groups. In the early 1930’s Erspamer was investigating the chemical responsible for smooth muscle tissue contrac- tions in rats.3 Erspamer’s investigation led to the successful isolation of 5-HT from the enteroch- romaffin cells in the gut from which he named it enteramine.3 Erspamer researched the role of 5-HT on smooth muscle contractions for many years and published volumes of literature under the enteramine title.3 Aside from being produced in large quantities the enterochromaffin cells in the gut by, 5-HT is stored in considerable quantities on blood platelets to aid in aggrega- tion.1,2 In 1948, 5-HT was isolated from blood serum by a research group consisting of Page, Rapport, and Green.1,3 Their search for a chemical component in blood responsible for hyper- tension would eventually lead to the isolation of 5-HT. The name serotonin was born from the marriage of the two ideas that 5-HT was isolated from blood serum (“ser”) and increases tone (“tonin”)
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