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Development of Novel Serotonin 5-HT6 and Dopamine D2 Receptor

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Development of Novel Serotonin 5-HT6 and Dopamine D2 Receptor Development of Novel Serotonin 5-HT6 and Dopamine D2 Receptor Ligands and MAO A Inhibitors Synthesis, Structure-Activity Relationships and Pharmacological Characterization Cecilia Mattsson UNIVERSITY OF GOTHENBURG Department of Chemistry and Molecular Biology University of Gothenburg 2013 DOCTORAL THESIS Submitted for partial fulfillment of the requirements for the degree of Doctor of Philosophy in Science with an Emphasis on Chemistry Development of Novel Serotonin 5-HT6 and Dopamine D2 Receptor Ligands and MAO A Inhibitors - Synthesis, Structure-Activity Relationships and Pharmacological Characterization Cecilia Mattsson © Cecilia Mattsson ISBN: 978-91-628-8741-4 http://hdl.handle.net/2077/33657 Department of Chemistry and Molecular Biology University of Gothenburg SE-412 96 Göteborg Sweden Printed by Ineko AB Kållered, 2013 In loving memory of my mother Abstract It is known since the 1950s that enhancement of the levels of the monoamines dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) in the brain will relieve the symptoms of major depression, and current therapies are still based on this mechanism. However, all available antidepressants today are still suffering from slow onset of therapeutic action, as well as adverse effects and lack of efficacy. Therefore, development of compounds with new mechanisms of action for treatment of depression is needed. One of the most important stages of the drug discovery process is the generation of lead compounds. Structure-activity relationships (SARs) are well integrated in modern drug discovery and have been used in the process of developing new leads. The tetrahydropyridine/piperidine indoles are known to affect multiple targets of the dopaminergic and serotonergic systems in the brain. This class of indoles can easily be modified and they possess the necessary properties for a lead, such as low molecular weight and high water solubility. This thesis is focused on further exploring the SAR around tetrahydropyridine/piperidine indoles by introduction of substituents and/or bioisosteric replacements of the indole core with the aim of developing novel compounds acting at the dopaminergic and serotonergic systems in the brain. By using in vivo and in vitro screening approaches, 5-HT type 6 receptor (5-HT6) agonists, DA type 2 receptor (DA D2) antagonists, 5-HT reuptake transporters (SERT) inhibitors, dual DA D2 antagonists/SERT inhibitors and finally reversible monoamine oxidase A (MAO A) inhibitors were identified after modifications of the chemical lead. In addition, the SAR of 6-substituted 3-(pyrrolidin-1-ylmethyl)chromen-2-ones (coumarin derivatives) were also investigated and were identified as selective and reversible MAO A inhibitors. Three compounds, i.e. the 5-HT6 agonist 81, the dual DA D2 antagonist/SERT inhibitor 158 and the MAO A inhibitor 134 have been identified to be of potential interest as novel antidepressants. Keywords: dopamine D2 receptor, serotonin reuptake transporter, monoamine oxidase, 5-HT6 receptor, DOPAC, 5-HIAA, 3-tetrahydropyridine indole, 3-piperidine indole, 3-(pyrrolidin-1- ylmethyl)chromen-2-one i Papers included in the thesis This thesis is based on the following publications and manuscript, which will be referred to in the thesis by their Roman numerals. I. 2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists Mattsson C, Sonesson C, Sandahl A, Greiner HE, Gassen M, Plaschke J, Leibrock J, Boettcher H. Bioorg Med Chem Lett. 2005, 15, 4230-4234 II. Structure-activity relationship of 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)- 1H-indole analogues as 5-HT6 receptor agonists Mattsson C, Svensson P, Boettcher H, Sonesson C. Eur J Med Chem. 2013, 63, 578-588 III. Systematic in vivo screening of a series of 1-propyl-4-aryl-piperidines against dopaminergic and serotonergic properties in rat brain: a scaffold-jumping approach Mattsson C, Andreasson T, Waters N, Sonesson C. J Med Chem. 2012, 55, 9735-9750 Correction: J Med Chem. 2013, 56, 4130-4133 IV. A novel series of 6-substituted 3-(pyrrolidin-1-ylmethyl)chromen-2-ones as selective monoamine oxidase (MAO) A inhibitors Mattsson C, Svensson P, Sonesson C. Eur J Med Chem. 2013, Submitted Reprints were made with permission from the journals. ii Contributions to the Papers I. Planned and synthesized most of the included compounds; interpreted results, and wrote the manuscript. II. Planned and synthesized most of the included compounds; interpreted results, and wrote the manuscript. Did not perform the conformation simulations. III. Planned and synthesized all of the included compounds; interpreted results, and wrote the manuscript. Did not perform the PLS correlations or in vivo studies. IV. Planned and synthesized all of the included compounds; interpreted results, and wrote the manuscript. Did not perform the docking study to the MAO A enzyme, conformation simulations or in vivo studies. iii Contents 1. Introduction ............................................................................................................................... 1 1.1. Neurotransmission....................................................................................................................... 1 1.2. Monoaminergic neurotransmitters .............................................................................................. 2 1.3. Monoamine synthesis and catabolism ......................................................................................... 3 1.4. The 5-HT neuron and receptor subtypes ..................................................................................... 4 1.4.1. The 5-HT6 receptor .............................................................................................................. 7 1.5. The dopamine neuron and receptor subtypes .............................................................................. 7 1.5.1. The dopamine D2 receptor ................................................................................................... 8 1.6. Monoamine oxidase (MAO) ....................................................................................................... 9 1.7. Depression ................................................................................................................................. 10 1.8. Structure-activity relationships ................................................................................................. 14 1.8.1. RU 24969 and analogs, SAR for 5-HT subtypes ................................................................ 14 1.8.2. 5-HT6 receptor agonists ..................................................................................................... 15 1.8.3. 5-HT6 receptor antagonists ................................................................................................ 16 1.8.4. RU 24969 analogs and SAR for the 5-HT6 receptor .......................................................... 17 1.8.5. Dopamine D2 receptor antagonists .................................................................................... 17 1.8.6. Dopamine D2 receptor agonists ......................................................................................... 18 1.8.7. Dopamine D2 receptor stabilizers ...................................................................................... 19 1.8.8. RU 24969 analogs and SAR for dopamine D2 receptors ................................................... 20 1.8.9. RU 24969 analogs and SAR for MAO inhibition ............................................................... 21 1.8.10. Coumarin analogs and SAR for MAO inhibition ............................................................. 21 2. Aims ........................................................................................................................................... 23 3. Chemistry ................................................................................................................................. 25 iv 3.1. Synthesis of 2-alkyl substituted 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles (Paper I, II) .. 25 3.1.1. Madelung synthesis of 2-alkyl-1H-indoles ......................................................................... 26 3.1.2. Transformation of functional groups on the indole core structure (Paper II) ................... 27 3.2. Synthesis of 1-propyl-4-aryl-piperidines (Paper III) ................................................................. 29 3.2.1. Synthesis of 3-(1-propyl-4-piperidyl)-1H-indazole (119) .................................................. 29 3.2.2. Synthesis of 4-(benzothiophen-2 and 3-yl)-1-propyl-piperidine derivatives ..................... 30 3.3. Synthesis of 6-subsituted 3-(pyrrolidin-1-ylmethyl)chromen-2-ones (Paper IV) ..................... 32 3.3.1. The Baylis-Hillman reaction .............................................................................................. 32 3.3.2. Baylis-Hillman reaction using 2-tetrahydropyranyl as a phenol protecting group .......... 34 4. Pharmacology ......................................................................................................................... 35 4.1. Methods ..................................................................................................................................... 35 4.1.1. In vitro assays .................................................................................................................... 35 4.1.2. In vivo models ...................................................................................................................
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