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    Synthesis, Pharmacological Characterization and QSAR

    Modelling of 4-Phenylpiperidines and 4-Phenylpiperazines

    Effects on the dopaminergic neurotransmission in vivo

    Fredrik Pettersson

    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

    UNIVERSITY OF GOTHENBURG

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    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

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    In loving memory of my mother Inga-Maj

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    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

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    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.

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    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

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    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)...............................................................