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Synthesis, Pharmacological Characterization and QSAR Modelling of 4-Phenylpiperidines and 4-Phenylpiperazines Effects on the Dopaminergic Neurotransmission in Vivo

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Synthesis, Pharmacological Characterization and QSAR Modelling of 4-Phenylpiperidines and 4-Phenylpiperazines Effects on the Dopaminergic Neurotransmission in Vivo View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Göteborgs universitets publikationer - e-publicering och e-arkiv Synthesis, Pharmacological Characterization and QSAR Modelling of 4-Phenylpiperidines and 4-Phenylpiperazines Effects on the dopaminergic neurotransmission in vivo Fredrik Pettersson UNIVERSITY OF GOTHENBURG Department of Chemistry and Molecular Biology University of Gothenburg 2012 DOCTORAL THESIS Submitted for partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry 1 Synthesis, Pharmacological Characterization and QSAR Modelling of 4-Phenyl-piperidines and 4-Phenylpiperazines - Effects on the dopaminergic neurotransmission in vivo Fredrik Pettersson © Fredrik Pettersson ISBN: 978-91-628-8588-5 http://hdl.handle.net/2077/31366 Department of Chemistry and Molecular Biology University of Gothenburg SE-412 96 Göteborg Sweden Printed by Kompendiet, Aidla Trading AB Göteborg, 2012 2 In loving memory of my mother Inga-Maj 3 4 Abstract The endogenous neurotransmitter dopamine (DA) is involved in several functions that are controlled from the central nervous system (CNS), for example behaviour, memory, cognition and reward. A disturbed dopaminergic neurotransmission may lead to many severe conditions, such as schizophrenia, attention deficit hyperactivity disorder (ADHD) or Parkinson's disease (PD). The dopamine receptors belong to the G-protein coupled receptors (GPCRs) and are divided into five distinct subtypes (D1-D5). These subtypes can be either of the D1- or D2-types based on their effect on the production of cyclic adenosine monophosphate (cAMP). The most common dopaminergic receptor used as target for pharmaceuticals is by far the D2 receptor and drugs acting as full agonists, partial agonists and antagonists at this receptor have been developed. In the search for new dopaminergic ligands, a set of 4-phenylpiperidines and 4- phenylpiperazines have been synthesized and their effects have been tested in both in vivo and in vitro assays. Starting with the known partial agonist 3-(1-benzylpiperidin-4-yl)phenol, stepwise structural modifications of functional groups afforded mainly D2 antagonists but with a conserved preference for binding to the agonist binding site and fast dissociation rates from the receptor. However, further modifications, including changes of the position of the aromatic substituent, indicated that other targets than the D2 receptor was involved and binding affinity studies later concluded that some of these compounds had MAO A inhibiting properties. In order to fully elucidate what structural properties are related to the different pharmacological responses, QSAR models with physicochemical descriptors set against each respective response were acquired by means of partial least square (PLS) regression. Models with high predictivity (Q2>0.53) were obtained and the interpretation of these models has provided an improved understanding of how structural modifications in this chemical class affect the response both in vivo and in vitro. The structural motifs that were investigated included the position and physicochemical properties of the aromatic substituent as well as the heterocycle being a piperazine or a piperidine. All these properties turned out to be significant for the different responses in some aspect. In addition, a strong correlation between the affinities to the D2 receptor and to MAO A and the levels of the metabolite DOPAC in striatum has been established. This led us to the conclusion that it is primarily interactions with these two targets that lead to the in vivo response observed for this class of compounds. _______________________________________________________________________________ Keywords: dopamine, D2, monoamine oxidase, DOPAC, in vivo, QSAR, dopaminergic stabilizer 5 Papers included in the thesis This thesis is based on the following publications and manuscripts: I. Synthesis and evaluation of a set of 4-phenylpiperidines and 4-phenylpiperazines as D2 receptor ligands and the discovery of the dopaminergic stabilizer 4-[3- (methylsulfonyl)phenyl]-1-propylpiperidine (Huntexil, Pridopidine, ACR16). Pettersson F, Pontén H, Waters N, Waters S, Sonesson C. J Med Chem. 2010 Mar 25; 53(6):2510-20. II. Synthesis and Evaluation of a Set of para-Substituted 4-Phenylpiperidines and 4- Phenylpiperazines as MAO Inhibitors. Pettersson F, Svensson P, Waters N, Waters S, Sonesson C. J Med Chem. 2012 Apr 12;55(7):3242-9 III. Synthesis, Pharmacological Evaluation and QSAR Modeling of mono-Substituted 4- Phenylpiperidines and 4-Phenylpiperazines Pettersson F, Svensson P, Waters N, Waters S, Sonesson C. Eur J Med Chem. 2012, Submitted IV. New quantum mechanically derived electronic principal properties of aromatic substituents. Sunesson Y, Norrby P. O., Pettersson F, Sonesson C and Svensson P. Manuscript Reprints were made with permission from the journals. 6 Contributions to the Papers I. Planned and synthesized most of the included compounds; Extracted the rawdata and calculated the correlations; interpreted results and wrote the manuscript II. Planned and synthesized most of the included compounds; Tabulated data from the rawdata and calculated the correlations and QSARs; interpreted results and wrote the manuscript III. Planned and synthesized most of the included compounds; Tabulated data from the rawdata and calculated the correlations and QSAR; interpreted results and wrote the manuscript IV. Provided the data set necessary for comparison; wrote parts of the manuscript, assisted with calculations of QSAR models; provided feed-back and managed the format 7 Contents 1. Introduction 1.1. Monoaminergic Neurotransmitters.........................................................................................1 1.1.1. Catecholamine Synthesis and Catabolism................................................................. 1 1.1.2. Monoamine Oxidases................................................................................................. 4 1.1.3. Dopamine Receptor Subtypes.................................................................................... 4 1.1.4. The Dopamine D2 Receptor....................................................................................... 5 1.2. Clinical Aspects of Dopaminergic Drugs.............................................................................. 6 1.2.1. Schizophrenia............................................................................................................. 6 1.2.2. Neurological Diseases................................................................................................ 7 1.3. Dopamine D2 Ligands............................................................................................................ 7 1.3.1. DA D2 Agonists........................................................................................................... 7 1.3.2. DA D2 Antagonists...................................................................................................... 8 1.3.3. DA D2 Partial Agonists............................................................................................... 9 1.3.4. Dopaminergic Stabilizers........................................................................................... 9 1.4. Structure Activity Relationships........................................................................................... 11 1.4.1. Phenylpiperidines and Phenylpiperazine.................................................................. 11 1.4.2. D2 Ligands................................................................................................................. 12 1.4.3. MAO Inhibitors......................................................................................................... 14 1.4.4. Quantitative structure activity relationships (QSARs).............................................. 15 1.4.5. Drug Design.............................................................................................................. 16 2. Aims............................................................................................................................................ 19 3. Chemistry 3.1. Original Synthetic Route to Pridopidine (Paper I)................................................................ 21 3.2. Suzuki Cross Coupling between Phenylbromides and 1-Pyridyl-4-boronic acid (Paper III)23 3.3. Buchwald-Hartwig Cross Coupling between Phenylbromides and Piperazines (Paper III). 24 3.4. Convertion of Functional Groups.......................................................................................... 26 3.4.1. Aniline to Morpholine (Paper II).............................................................................. 26 3.4.2. Phenols to Mesylates and Triflates (Paper III)......................................................... 26 3.4.3. Triflate to Nitrile (Paper III) .................................................................................... 27 3.4.4. Phenols to Alkoxy-groups (Paper II and III) ............................................................ 28 4. Pharmacology 4.1. Methods................................................................................................................................. 29 4.1.1. In vitro models........................................................................................................... 29 4.1.2. In vivo models............................................................................................................ 30
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