DOCSLIB.ORG

Synthesis and Pharmacological Characterization of New Histamine

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Synthesis and pharmacological characterization of new histamine H1-/H4-receptor ligands derived from the atypical antipsychotic drug Clozapine Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) der Naturwissenschaftlichen Fakultät IV – Chemie und Pharmazie – der Universität Regensburg vorgelegt von Susanne Gobleder aus Eichstätt 2014 Die vorliegende Arbeit entstand in der Zeit von Juli 2010 bis Mai 2014 unter der Leitung von Frau PD Dr. Andrea Straßer und Herrn Prof. Dr. Sigurd Elz am Institut für Pharmazie der Naturwissenschaftlichen Fakultät IV - Chemie und Pharmazie - der Universität Regensburg. Das Promotionsgesuch wurde eingereicht im Mai 2014. Tag der mündlichen Prüfung: 23. Mai 2014 Prüfungsausschuss: Prof. Dr. A. Buschauer (Vorsitzender) PD Dr. A. Straßer (Erstgutachterin) Prof. Dr. S. Elz (Zweitgutachter) Prof. Dr. J. Heilmann (Drittprüfer) Author’s Declaration The author declares that the work presented in this thesis was written by none other than herself. Apart from were indicated, all work was performed or supervised by the author. Molecular dynamics simulations described in Chapter 4.4.1.2 and Figure 4.5 were performed by PD Dr. A. Straßer and Dr. H.-J. Wittmann (Department of Pharmaceutical / Medicinal Chemistry II, University of Regensburg, Germany; Faculty of Chemistry and Pharmacy, University of Regensburg, Germany). Competition binding assays at dopamine, serotonin and muscarine receptors described in Chapter 4.4.3 were performed by Prof. Dr. P. Gmeiner, Dr. H. Hübner and Coworkers (Department of Pharmaceutical Chemistry, Friedrich Alexander University Erlangen – Nürnberg, Germany). Danksagungen An dieser Stelle möchte ich mich bedanken bei: Frau PD Dr. Andrea Straßer für die wissenschaftlichen Anregungen und die konstruktive Kritik bei der Durchsicht dieser Arbeit, für die Erstellung des Erstgutachtens sowie für die strukturierte, gewissenhafte und zielorientierte Betreuung während der gesamten Promotionszeit, Herrn Prof. Dr. Sigurd Elz für die Vergabe des interessanten und herausfordernden Promotionsthemas, für seine geduldige Hilfestellung bei der Interpretation der organpharmakologischen Daten am Meerschweinchen-Ileum und für die Erstellung des Zweitgutachtens, Herrn Prof. Dr. Jörg Heilmann für seine Bereitschaft, das Amt des Drittprüfers zu übernehmen, Herrn Prof. Dr. Armin Buschauer für die Möglichkeit zur Teilnahme an den Lehrstuhlseminaren seines Arbeitskreises sowie zur Durchführung der pharmakologischen Arbeiten an seinem Lehrstuhl und dafür, dass er sich bereit erklärt hat, den Vorsitz der Prüfungskommission zu übernehmen, Herrn Prof. Dr. Jens Schlossmann für die Zurverfügungstellung von Laborräumen und -verbrauchsmaterialien zur Durchführung der Radioligand-Bindungsassays an seinem Lehrstuhl, Herrn Dr. Hans-Joachim Wittmann für die Erstellung der Molecular Dynamics Simulationen am Histamin H1- und H4-Rezeptor, Frau Maria Beer-Krön für die Bereitstellung der Sf9-Zellen, ihre außerordentliche Hilfsbereitschaft bei der Membranpräparation sowie für ihre Unterstützung bei der Durchführung der steady-state [33P]GTPase- und [35S]GTPγS Assays, Frau Christine Braun und Frau Kerstin Röhrl für die zuverlässige Durchführung der organpharmakologischen Testungen am Meerschweinchen-Ileum, Frau Gertraud Wilberg für die Bereitstellung der Sf9-Zellen sowie für ihre Hilfsbereitschaft in allen Bereichen der pharmakologischen Labortätigkeiten, Frau Uta Hasselmann für ihre tatkräftige Unterstützung bei organisatorischen Problemen aller Art und für ihre ansteckende gute Laune, allen Mitarbeitern der analytischen Abteilungen der Fakultät für die Aufnahme der NMR- und Massenspektren sowie für die Durchführung der Elementaranalysen, allen Mitgliedern der Lehrstühle Pharmazeutische Chemie I und Pharmazeutische Chemie II für das angenehme Arbeitsklima, die kollegiale Zusammenarbeit und die stetige Hilfsbereitschaft bei chemischen Problemstellungen (hierbei gilt der Dank insbesondere Herrn Dr. Herwig Pongratz und Herrn Dr. Andreas Sellmer), meinen Kollegen Frau Bernadette Streifinger und Herrn Michel Leonhard für die geduldige Hilfe bei der Formatierung dieser Arbeit, meinem Kollegen Herrn Thomas Dang-Lieu für die Unterstützung bei Netzwerk- und Computerproblemen, Frau Franziska Naporra für die engagierte Mitarbeit im Labor im Rahmen ihres Forschungspraktikums, meinem Laborkollegen Herrn Steffen Pockes für eine fabelhafte musikalische Untermalung der gemeinsamen Laborzeit (möge sich die Discokugel immer drehen) sowie für die gute Freundschaft während der Promotion, meinen Kolleginnen in der Marien Apotheke Schierling, die mir durch ihr herzliches Betriebsklima eine angenehme Abwechslung zum Laboralltag geboten haben, meinen Eltern für ihre liebevolle Fürsorge, ihre Ermutigung und ihre Unterstützung während des Studiums und der Promotion, und vor allem meinem Freund Tommy für seine Geduld, sein Verständnis und seinen bedingungslosen Rückhalt in allen Lebenslagen. Scientific presentations . EFMC-ISMC 21st International Symposium on Medicinal Chemistry, Brussels (Belgium), 05. – 09.09.2010 Poster presentation. E. Wagner, S. Gobleder and A. Straßer. “Synthesis, pharmacological characterization and molecular modelling of dual Histamine H1-/H4-receptor antagonists.” . 5th Summer School “Medicinal Chemistry”, Regensburg (Germany), 13. – 15.09.2010 Poster presentation. E. Wagner, S. Gobleder and A. Straßer. “Synthesis, pharmacological characterization and molecular modelling of dual Histamine H1-/H4-receptor antagonists.” . Joint Meeting of the Austrian and German Pharmaceutical Societies, Innsbruck (Austria), 20. – 23.09.2011 Poster presentation. S. Gobleder, S. Elz and A. Straßer. “Synthesis and pharmacology of Clozapine-derived Histamine H1-/H4-receptor ligands.” . 6th Summer School “Medicinal Chemistry”, Regensburg (Germany), 26. – 28.09.2012 Oral poster presentation. S. Gobleder, S. Elz and A. Straßer. “New Clozapine derived Histamine H1-/H4-receptor ligands as possible treatment of type-I- allergic diseases.” . Annual meeting of the German Pharmaceutical Society, Greifswald (Germany), 10. – 13.10.2012 Poster presentation. S. Gobleder, H.-J. Wittmann, S. Elz and A. Straßer. “New Clozapine derived Histamine H1-/H4-receptor ligands as possible treatment of type-I-allergic diseases.” . Annual meeting of the German Pharmaceutical Society, Freiburg (Germany), 09. – 11.10.2013 Poster presentation. S. Gobleder, H.-J. Wittmann, S. Elz and A. Straßer. “New Clozapine derived dimeric Histamine H1-/H4-receptor ligands and their pharmacological characterization.” Contents ___________________________________________________________________ CONTENTS 1. INTRODUCTION _________________________________________________ 2 1.1. The G-Protein coupled receptors (GPCRs) ______________________________________ 2 1.1.1. Structure and classification of GPCRs _______________________________________ 2 1.1.2. GPCRs on a molecular level _______________________________________________ 3 1.1.3. The G-protein cycle ______________________________________________________ 4 1.1.4. Signal transduction pathways of GPCRs _____________________________________ 6 1.1.5. Receptor activation and ligand classification __________________________________ 8 1.1.6. GPCR oligomerization and dimerization: bivalent ligands and their interaction with the receptors _____________________________________________________________ 10 1.2. Histamine and the histamine receptor family ___________________________________ 12 1.2.1. The histamine H1 receptor _______________________________________________ 13 1.2.2. The histamine H2 receptor _______________________________________________ 17 1.2.3. The histamine H3 receptor _______________________________________________ 19 1.2.4. The histamine H4 receptor _______________________________________________ 23 1.3. Antipsychotic drugs __________________________________________________________ 26 1.3.1. Classification __________________________________________________________ 26 1.3.2. Clozapine and its interaction with multiple molecular targets (“dirty drug” problem) ___ 28 1.4. References ___________________________________________________________________ 30 2. SCOPE AND OBJECTIVES _________________________________ 46 References ___________________________________________________________________ 49 3. CHEMICAL SECTION ______________________________________ 52 3.1. Ligand design related to VUF 6884 (Smits et al., 2006) __________________________ 52 3.2. Synthesis of the “open” phenylbenzamidines: opening up the rigid aromatic ring system in the center of the molecule __________________________________________ 53 3.2.1. VUF 6884 reduced to the core: (E)-N-(2-aminoethyl)-N'-phenylbenzamidine derivatives 53 3.2.2. “Open” VUF 6884 derivatives with modified substitution pattern: detecting the influence of kind and position of the substituents ________________________________________ 54 3.2.3. Acylated open VUF 6884 derivatives: an attempt to increase the hH4R affinity _______ 58 3.3. Synthesis of the closed VUF 6884 derivatives: return to a rigid aromatic ring system in the center of the molecule __________________________________________________ 61 Contents ___________________________________________________________________ 3.3.1. “Ring-closed” VUF 6884 derivatives with modified substitution pattern: determining the key role of the closed central heterocycle in synergy with the substitution pattern ________ 62 3.3.2. “Closed” VUF 6884 derivatives with a modified piperazine moiety: exchanging N- methylpiperazine
Recommended publications
  • The Histamine H4 Receptor: a Novel Target for Safe Anti-Inflammatory

    The Histamine H4 Receptor: a Novel Target for Safe Anti-Inflammatory

    GASTRO ISSN 2377-8369 Open Journal http://dx.doi.org/10.17140/GOJ-1-103 Review The Histamine H4 Receptor: A Novel Target *Corresponding author Maristella Adami, PhD for Safe Anti-inflammatory Drugs? Department of Neuroscience University of Parma Via Volturno 39 43125 Parma Italy * 1 Tel. +39 0521 903943 Maristella Adami and Gabriella Coruzzi Fax: +39 0521 903852 E-mail: [email protected] Department of Neuroscience, University of Parma, Via Volturno 39, 43125 Parma, Italy Volume 1 : Issue 1 1retired Article Ref. #: 1000GOJ1103 Article History Received: May 30th, 2014 ABSTRACT Accepted: June 12th, 2014 th Published: July 16 , 2014 The functional role of histamine H4 receptors (H4Rs) in the Gastrointestinal (GI) tract is reviewed, with particular reference to their involvement in the regulation of gastric mucosal defense and inflammation. 4H Rs have been detected in different cell types of the gut, including Citation immune cells, paracrine cells, endocrine cells and neurons, from different animal species and Adami M, Coruzzi G. The Histamine H4 Receptor: a novel target for safe anti- humans; moreover, H4R expression was reported to be altered in some pathological conditions, inflammatory drugs?. Gastro Open J. such as colitis and cancer. Functional studies have demonstrated protective effects of H4R an- 2014; 1(1): 7-12. doi: 10.17140/GOJ- tagonists in several experimental models of gastric mucosal damage and intestinal inflamma- 1-103 tion, suggesting a potential therapeutic role of drugs targeting this new receptor subtype in GI disorders, such as allergic enteropathy, Inflammatory Bowel Disease (IBD), Irritable Bowel Syndrome (IBS) and cancer. KEYWORDS: Histamine H4 receptor; Stomach; Intestine.
  • Table 2. Significant

    Table 2. Significant

    Table 2. Significant (Q < 0.05 and |d | > 0.5) transcripts from the meta-analysis Gene Chr Mb Gene Name Affy ProbeSet cDNA_IDs d HAP/LAP d HAP/LAP d d IS Average d Ztest P values Q-value Symbol ID (study #5) 1 2 STS B2m 2 122 beta-2 microglobulin 1452428_a_at AI848245 1.75334941 4 3.2 4 3.2316485 1.07398E-09 5.69E-08 Man2b1 8 84.4 mannosidase 2, alpha B1 1416340_a_at H4049B01 3.75722111 3.87309653 2.1 1.6 2.84852656 5.32443E-07 1.58E-05 1110032A03Rik 9 50.9 RIKEN cDNA 1110032A03 gene 1417211_a_at H4035E05 4 1.66015788 4 1.7 2.82772795 2.94266E-05 0.000527 NA 9 48.5 --- 1456111_at 3.43701477 1.85785922 4 2 2.8237185 9.97969E-08 3.48E-06 Scn4b 9 45.3 Sodium channel, type IV, beta 1434008_at AI844796 3.79536664 1.63774235 3.3 2.3 2.75319499 1.48057E-08 6.21E-07 polypeptide Gadd45gip1 8 84.1 RIKEN cDNA 2310040G17 gene 1417619_at 4 3.38875643 1.4 2 2.69163229 8.84279E-06 0.0001904 BC056474 15 12.1 Mus musculus cDNA clone 1424117_at H3030A06 3.95752801 2.42838452 1.9 2.2 2.62132809 1.3344E-08 5.66E-07 MGC:67360 IMAGE:6823629, complete cds NA 4 153 guanine nucleotide binding protein, 1454696_at -3.46081884 -4 -1.3 -1.6 -2.6026947 8.58458E-05 0.0012617 beta 1 Gnb1 4 153 guanine nucleotide binding protein, 1417432_a_at H3094D02 -3.13334396 -4 -1.6 -1.7 -2.5946297 1.04542E-05 0.0002202 beta 1 Gadd45gip1 8 84.1 RAD23a homolog (S.
  • Histamine Receptors

    Histamine Receptors

    Tocris Scientific Review Series Tocri-lu-2945 Histamine Receptors Iwan de Esch and Rob Leurs Introduction Leiden/Amsterdam Center for Drug Research (LACDR), Division Histamine is one of the aminergic neurotransmitters and plays of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit an important role in the regulation of several (patho)physiological Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The processes. In the mammalian brain histamine is synthesised in Netherlands restricted populations of neurons that are located in the tuberomammillary nucleus of the posterior hypothalamus.1 Dr. Iwan de Esch is an assistant professor and Prof. Rob Leurs is These neurons project diffusely to most cerebral areas and have full professor and head of the Division of Medicinal Chemistry of been implicated in several brain functions (e.g. sleep/ the Leiden/Amsterdam Center of Drug Research (LACDR), VU wakefulness, hormonal secretion, cardiovascular control, University Amsterdam, The Netherlands. Since the seventies, thermoregulation, food intake, and memory formation).2 In histamine receptor research has been one of the traditional peripheral tissues, histamine is stored in mast cells, eosinophils, themes of the division. Molecular understanding of ligand- basophils, enterochromaffin cells and probably also in some receptor interaction is obtained by combining pharmacology specific neurons. Mast cell histamine plays an important role in (signal transduction, proliferation), molecular biology, receptor the pathogenesis of various allergic conditions. After mast cell modelling and the synthesis and identification of new ligands. degranulation, release of histamine leads to various well-known symptoms of allergic conditions in the skin and the airway system. In 1937, Bovet and Staub discovered compounds that antagonise the effect of histamine on these allergic reactions.3 Ever since, there has been intense research devoted towards finding novel ligands with (anti-) histaminergic activity.
  • H4R) and the Human Free Fatty Acid Receptor 4 (FFA4)

    H4R) and the Human Free Fatty Acid Receptor 4 (FFA4)

    Evaluation of signalling and phosphorylation responses of the human histamine H4 receptor (H4R) and the human free fatty acid receptor 4 (FFA4) Thesis Submitted for the Degree of Doctor of Philosophy at the University of Leicester By Sajjad Ali Riaz Department of Molecular and Cellular Biology University of Leicester May 2016 Abstract The knowledge that G protein-coupled receptors (GPCRs) are regulated by phosphorylation in a process that results in the recruitment of arrestins, leading to receptor desensitisation is now well known. The histamine H4 receptor (H4R) and the free fatty acid receptor 4 (FFA4) are family A GPCRs that both have the ability to become phosphorylated in their third intracellular loops and C-terminal tails by kinases found in the cytosolic milieu of the cells and tissues they are expressed in. Investigations into the phosphorylation status of the histamine H4 receptor have revealed a receptor that is highly phosphorylated even in the basal state. The endogenous, full agonist for the human H4R, histamine, induced a robust increase in receptor phosphorylation. However, the β-arrestin-biased agonist JNJ7777120 did not. Extending this study using mass spectrometry revealed the individual sites of phosphorylation. Histamine and JNJ7777120 also caused H4R internalisation. Our data suggests a similar level of endocytosis induced by histamine and JNJ7777120 at 5 or 30 min stimulation. Thus, we show that JNJ7777120, while previously demonstrating its differing effects on H4R signalling, also shows differences in the phosphorylation of the H4R when compared to histamine. Using the wild type FFA4 receptor and its phosphorylation-deficient mutants, we show the importance of phosphorylation in the recruitment of arrestin to the receptor as well as delineating G protein-dependent and independent downstream signalling pathways.
  • Untersuchungen Zur Transmission Des Über Den Histamin-4-Rezeptor Induzierten Juckreizsignals

    Untersuchungen Zur Transmission Des Über Den Histamin-4-Rezeptor Induzierten Juckreizsignals

    Tierärztliche Hochschule Hannover Untersuchungen zur Transmission des über den Histamin-4-Rezeptor induzierten Juckreizsignals INAUGURAL - DISSERTATION zur Erlangung des Grades einer Doktorin der Veterinärmedizin - Doctor medicinae veterinariae - (Dr. med. vet.) vorgelegt von Jenny Wilzopolski Brunsbüttel Hannover 2017 Wissenschaftliche Betreuung: Prof. Dr. med. vet. Manfred Kietzmann Institut für Pharmakologie, Toxikologie und Pharmazie 1. Gutachter: Prof. Dr. med. vet. Manfred Kietzmann 2. Gutachter: Prof. Dr. med. vet. Reinhard Mischke Tag der mündlichen Prüfung: 06.11.2017 Die Arbeit wurde gefördert durch die Deutsche Forschungsgemeinschaft. I "Leicht ist das Leben für keinen von uns. Doch was nützt das, man muß Ausdauer haben und Zutrauen zu sich selbst. Man muß daran glauben, für eine bestimmte Sache begabt zu sein, und diese Sache muß man erreichen, koste es was es wolle." -Marie Curie- Für meine Familie II III Inhaltsverzeichnis Inhaltsverzeichnis Inhaltsverzeichnis ...................................................................................................................... iv Abbildungsverzeichnis ............................................................................................................ viii Tabellenverzeichnis .................................................................................................................... x Abkürzungsverzeichnis ............................................................................................................ xii 1. Einleitung .............................................................................................................................
  • G Protein-Coupled Receptors

    G Protein-Coupled Receptors

    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
  • G Protein‐Coupled Receptors

    G Protein‐Coupled Receptors

    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology (2019) 176, S21–S141 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors Stephen PH Alexander1 , Arthur Christopoulos2 , Anthony P Davenport3 , Eamonn Kelly4, Alistair Mathie5 , John A Peters6 , Emma L Veale5 ,JaneFArmstrong7 , Elena Faccenda7 ,SimonDHarding7 ,AdamJPawson7 , Joanna L Sharman7 , Christopher Southan7 , Jamie A Davies7 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia 3Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK 4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 5Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 6Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 7Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website.
  • International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

    International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

    1521-0081/67/3/601–655$25.00 http://dx.doi.org/10.1124/pr.114.010249 PHARMACOLOGICAL REVIEWS Pharmacol Rev 67:601–655, July 2015 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: ELIOT H. OHLSTEIN International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors Pertti Panula, Paul L. Chazot, Marlon Cowart, Ralf Gutzmer, Rob Leurs, Wai L. S. Liu, Holger Stark, Robin L. Thurmond, and Helmut L. Haas Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry (H.S.) and Institute of Neurophysiology, Medical Faculty (H.L.H.), Heinrich-Heine-University Duesseldorf, Germany; and Janssen Research & Development, LLC, San Diego, California (R.L.T.) Abstract ....................................................................................602 Downloaded from I. Introduction and Historical Perspective .....................................................602 II. Histamine H1 Receptor . ..................................................................604 A. Receptor Structure
  • Histamine H4 Receptor Regulates IL-6 and INF-Γ Secretion in Native

    Histamine H4 Receptor Regulates IL-6 and INF-Γ Secretion in Native

    Peng et al. Clin Transl Allergy (2019) 9:49 https://doi.org/10.1186/s13601-019-0288-1 Clinical and Translational Allergy LETTER TO THE EDITOR Open Access Histamine H4 receptor regulates IL-6 and INF-γ secretion in native monocytes from healthy subjects and patients with allergic rhinitis Hua Peng1†, Jian Wang1†, Xiao Yan Ye2,3, Jie Cheng1, Cheng Zhi Huang1, Li Yue Li2,3, Tian Ying Li2,3 and Chun Wei Li2,3* Abstract Histamine H1 receptor (H1R) and histamine H4 receptor (H4R) are essential in allergic infammation. The roles of H4R have been characterized in T cell subsets, whereas the functional properties of H4R in monocytes remain unclear. In the current study, the responses of H4R in peripheral monocytes from patients with allergic rhinitis (AR) were investigated. The results confrmed that H4R has the functional efects of mediating cytokine production (i.e., down- regulating IFN-γ and up-regulating IL-6) in cells from a monocyte cell line following challenge with histamine. We demonstrated that when monocytes from AR patients were stimulated with allergen extracts of house dust mite (HDM), IFN-γ secretion was dependent on H4R activity, but IL-6 secretion was based on H1R activity. Furthermore, a combination of H1R and H4R antagonists was more efective at blocking the infammatory response in monocytes than treatment with either type of antagonist alone. Keywords: Histamine H4 receptor, Histamine H1 receptor, Allergic rhinitis, Native human monocyte, Th1 and Th2 cytokines To the editor of H4R in monocyte-derived macrophages and dendritic Allergic rhinitis (AR) has long been considered to be cells in atopic dermatitis [6, 7]; in addition, two stud- mainly mediated by activation of histamine H1 receptor ies have indicated the functional roles of H4R in native (H1R) [1], although the use of histamine H1R antago- monocytes from healthy subjects by inhibiting CCL2 nists to treat this disease has produced unsatisfactory production or IL-12p70 secretion [8, 9].
  • 2 12/ 35 74Al

    2 12/ 35 74Al

    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 22 March 2012 (22.03.2012) 2 12/ 35 74 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/16 (2006.01) A61K 9/51 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 9/14 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP201 1/065959 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 14 September 201 1 (14.09.201 1) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (25) Filing Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (26) Publication Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/382,653 14 September 2010 (14.09.2010) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, NANOLOGICA AB [SE/SE]; P.O Box 8182, S-104 20 ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Stockholm (SE).
  • Proteostasis of Glial Intermediate Filaments: Disease Models, Tools, and Mechanisms

    Proteostasis of Glial Intermediate Filaments: Disease Models, Tools, and Mechanisms

    PROTEOSTASIS OF GLIAL INTERMEDIATE FILAMENTS: DISEASE MODELS, TOOLS, AND MECHANISMS Rachel Anne Battaglia A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Cell Biology and Physiology in the School of Medicine. Chapel Hill 2021 Approved by: Natasha T. Snider Carol Otey Keith Burridge Douglas Cyr Mohanish Deshmukh Damaris Lorenzo i © 2021 Rachel Anne Battaglia ALL RIGHTS RESERVED ii ABSTRACT Rachel Anne Battaglia: Proteostasis of Glial Intermediate Filaments: Disease Models, Tools, and Mechanisms (Under the direction of Natasha T. Snider) Astrocytes are a major glial cell type that is crucial for the health and maintenance of the Central Nervous System (CNS). They fulfill diverse functions, including synapse formation, neurogenesis, ion homeostasis, and blood brain barrier formation. Intermediate filaments (IFs) are components of the astrocyte cytoskeleton that support many of these functions in healthy individuals. However, upon cellular stress or genetic mutations, IF proteins are prone to accumulation and aggregation. These processes are thought to contribute to disease pathogenesis of different tissue-specific disorders, but therapeutic targeting of IFs is hindered by a lack of pharmacological tools to modulate their assembly and disassembly states. Moreover, the mechanisms that govern the formation and dissolution of IF aggregates are poorly defined. In this dissertation, I investigate IF aggregates called Rosenthal fibers (RFs), which form in astrocytes of patients with two pediatric neurodegenerative diseases, Alexander disease (AxD) and Giant Axonal Neuropathy (GAN). My aim was to gain a better understanding of the mechanisms of how astrocyte IF protein aggregates form and interrogate the role of post- translational modifications (PTMs) in this process.
  • Programme and Abstracts Book

    Programme and Abstracts Book

    0 33. Annual Meeting European Histamine Research Society 28. April – 2. May 2004 Düsseldorf / Köln, Germany 1 Dear Histaminologists 28. April 2004 Welcome to the 33rd Annual Meeting of the European Histamine Research Society at the Kardinal Schulte Haus near Cologne. Many of you have seen Cologne at the occasion of the 1993 meeting. The host institution is now located 30 km to the north: Department of Neurophysiology, Heinrich-Heine-University, Düsseldorf. Heinrich Heine, the patron of our University and one of our major poets, was born in Düsseldorf in 1797, he died in Paris in 1856. He wrote romantic poems often with a unique and unusual ironic or disillusioning twist at the end. He was the founder of the modern feuilleton and wrote a bit caustic about his birthplace. Nevertheless, Düsseldorf is worth a visit, there is interesting recent architecture (e.g. O’Gehry) a fine art collection (20th century) and a jewel in the south: Benrath castle and park (1777). We meet at the south end of “Bergisches Land” that we will explore during our excursion. The chemical industry founded by Bayer and Leverkus is around us: Leverkusen and Wuppertal. Düsseldorf is a village (1/2 Mio inhabitants) located at the mouth of the river Düssel into the Rhine. A formerly romantic part of the Düssel-valley has been praised by the 17th century pastor Neander and is consequently called the Neanderthal, the valley where the first bones of the Neandertal-man were found in 1856. Schloss Burg is a mediaeval castle, its 12th century appearance has been restored and a museum recalls the long bygone times.