University of Groningen Synthesis and Evaluation of Dopaminergic

University of Groningen Synthesis and evaluation of dopaminergic prodrugs designed for transdermal iontophoretic drug delivery Graan, Jeroen de IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2012 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Graan, J. D. (2012). Synthesis and evaluation of dopaminergic prodrugs designed for transdermal iontophoretic drug delivery: highly water-soluble amino acid ester prodrugs applicable for the treatment of Parkinson's disease. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). 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Download date: 29-09-2021 Synthesis and evaluation of dopaminergic prodrugs designed for transdermal iontophoretic drug delivery Highly water-soluble amino acid ester prodrugs applicable for the treatment of Parkinson's disease Jeroen de Graan The research project described in this thesis was carried out at the Department of Medicinal Chemistry, Groningen Research Institute of Pharmacy (Faculty of Mathematics and Natural Sciences, University of Groningen) in collaboration with the Division of Drug Delivery Technology of the Leiden/Amsterdam Center for Drug Research, Leiden University. This research is supported by the Dutch Technology Foundation STW, which is part of the Netherlands Organisation for Scientific Research (NWO) and partly funded by the Ministry of Economic Affairs, Agriculture and Innovation (project number STW LKG6507) The publication of this thesis was also financially supported by the University of Groningen and Axon Medchem B.V. Cover Design: Jeroen de Graan Layout: Jeroen de Graan Printed by: BOXPress BV, Proefschriftmaken.nl ISBN: 978-90-367-5499-6 ISBN: 978-90-367-5498-9 (electronic version) Copyright © 2012 by Jeroen de Graan. All rights reserved. No parts of this thesis may be reproduced or transmitted in any form or by any means without written permission of the author. RIJKSUNIVERSITEIT GRONINGEN Synthesis and evaluation of dopaminergic prodrugs designed for transdermal iontophoretic drug delivery Highly water-soluble amino acid ester prodrugs applicable for the treatment of Parkinson's disease Proefschrift ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. E. Sterken, in het openbaar te verdedigen op maandag 21 mei 2012 om 14.30 uur door Jeroen de Graan geboren op 15 februari 1980 te Lima, Peru Promotor: Prof. dr. B.H.C. Westerink Copromotor: Dr. D. Dijkstra Beoordelingscommissie: Prof. dr. H.W. Frijlink Prof. dr. ir. A.J. Minnaard Prof. dr. C.G. Kruse To my grandparents, parents and sister Table of contents Chapter 1 Introduction 9 Chapter 2 Synthesis of a series of prodrugs of the potent 61 dopamine (DA) D2 agonist 5-hydroxy-2-(N,N,-di-n- propylamino)tetralin (5-OH-DPAT), compounds designed for iontophoretic transdermal delivery Chapter 3 Chemical stability and enzymatic hydrolysis of a 91 series of amino acid ester prodrugs of the dopamine D2 agonist 5-OH-DPAT Chapter 4 The pharmacokinetics and pharmacological effect 113 of (S)-5-OH-DPAT following controlled delivery with transdermal iontophoresis. Chapter 5 The in vitro and in vivo evaluation of new 141 synthesized prodrugs of 5-OH-DPAT for iontophoretic delivery Chapter 6 Synthesis and chemical stability studies of dipeptide 167 ester prodrugs of (S)-5-OH-DPAT Chapter 7 Structural analogs of 5-OH-DPAT: synthesis and 187 their influence on in vitro transdermal iontophoretic delivery Chapter 8 Synthesis, and chemical stability studies of prodrugs 207 of (-)-8-OH-DPAC, a potent dopamine D2 agonist Chapter 9 Summary and general discussion 229 Appendix List of abbreviations 235 Samenvatting 239 Samenvatting voor niet ingewijden 244 Dankwoord 246 List of publications 249 1 Introduction INTRODUCTION 1.1 DOPAMINE AND ITS FUNCTION IN THE CENTRAL NERVOUS SYSTEM The nervous system is divided into the central nervous system (CNS) and the peripheral nervous system. Neurotransmission between nerve cells is realized by generation of action potentials. This generally results in a release of a chemical neurotransmitter which stimulates or inhibits another cell. An example of such a chemical neurotransmitter is dopamine (DA).1 DA (2-(3,4-dihydroxyphenyl)ethylamine) is a catecholamine neurotransmitter found in neurons of both the CNS and peripheral nervous system. Although DAergic neurons correspond to less than 1% of the total number of brain neurons, they play a significant role in brain functions, such as motivation, working memory and motor behavior. A high concentration of the DA is found in the striatum, which forms an important part of the extrapyramidal system and is known to control motor activity.2, 3 The DA neurons in this pathway play an important role in the pathophysiology and treatment of Parkinson’s disease. DA is formed from its precursor L-DOPA (3,4-dihydroxy-L-phenylalanine) by aromatic-L- amino-acid decarboxylase (AAAD) (Scheme 1.1). The clearance of DA occurs by re-uptake into the presynaptic neuron, or by metabolic inactivation by monoamine oxidase B (MAO- B) as well as catechol-O-methyltransferase (COMT).4 Homovanillic acid (HVA, 4- hydroxy-3-methoxyphenylacetic acid) is the final and main metabolic break-down product of DA in the human brain. Most of the brain DA is first attacked by MAO-B to give 3,4- dihydroxyphenylacetic acid (DOPAC) and subsequently attacked by COMT to form HVA. Another route occurs via initial O-methylation by COMT to give 3-methoxytyramine (3- MT) followed by oxidative deamination by MAO-B to give HVA.5 Scheme 1.1 Main pathway of biosynthesis and catabolism of DA in the mammalian organism.5 10 CHAPTER 1 1.2 ANATOMY OF THE DOPAMINE SYSTEM Techniques to detect DA neurons and localize DA receptors have identified distinct DA pathways in the brain of which the nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular are the major pathways (Figure 1.1).4, 6 The highly organized nigrostriatal pathway is the major DA pathway of the brain and originates from the substantia nigra pars compacta (SNc) projecting to the corpus striatum of the basal nuclei, whose function is to produce a smooth coordination in movement. A second prominent DA pathway is the mesolimbic pathway, which has cell bodies in the ventral tegmental area and sends axons to the limbic system, whose primary responsibility is the regulation of reward and related emotion-based behaviour.1, 3, 6, 7 The mesocortical pathway has DAergic projections to the prefrontal cortex and modulates cognitive behaviour7, learning and memory.8 The tuberoinfundibular pathway has its cell bodies in the hypothalamus and projects toward the pituitary gland.9 Figure 1.1 Nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular DAergic pathways.4, 9 11 INTRODUCTION 1.3 DOPAMINE RECEPTORS DA exerts its action by binding to specific membrane DA receptors. Five distinct DA receptors have been subdivided into two subfamilies, D1- and D2-like, on the basis of their 8 biochemical and pharmacological properties. The D1 and D5 receptors are classified as 10 “D1-like” and the D2, D3 and D4 receptors are considered to be “D2-like”. 1.3.1 G protein-coupled receptor structure The DA receptor subtypes belong to the large G protein-coupled receptor (GPCR) family. The receptors are characterized structurally by the presence of 7 transmembrane domains which form the DA binding site.4, 10 Members of the same DA subfamily share considerable homology in their transmembrane domains (Figure 1.2).11 Figure 1.2 DA receptor structure.11 1.3.2 Second messenger pathways The best-described effects mediated by DA are the activation or inhibition of the cyclic adenosine monophosphate (cAMP) pathway via adenylate cyclase (AC), and modulation of Ca2+ signalling.8 Two distinct guanosine triphosphate(GTP)-binding proteins regulate cAMP formation: one is specific for stimulation of AC (Gs), and the other is specific for its 1, 4, 8, 9, 12 10 inhibition (Gi). All D1-like receptors stimulate cAMP accumulation and the D2- like receptors inhibit the activity of AC.8, 10, 11, 13, 14 1.3.3 Distribution of the dopamine receptor families in the brain D1- and D2-like receptors have similar regional distributions in rat, monkey, and human brain, with the highest concentrations in striatum, olfactory bulb, and substantia nigra (SN). The DA receptor subtypes appear to be expressed by distinct populations of GABAergic 12 CHAPTER 1 (GABA, γ-aminobutyric acid) neurons: the DA D1

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