DOCSLIB.ORG

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

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
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 .............................................................................................................................. 1 2. Literaturübersicht ................................................................................................................ 4 2.1. Juckreiz ................................................................................................................................ 4 2.1.1. Ursachen ........................................................................................................................... 4 2.1.1.1. Botenstoffe .................................................................................................................... 5 2.1.2. Mechanismen und Neurophysiologie ............................................................................... 7 2.2. Histamin ............................................................................................................................ 11 2.3. Histaminrezeptoren ........................................................................................................... 12 2.3.1. Intrazellulärer Signalweg des histamininduzierten Juckreizes in sensorischen Neuronen .................................................................................................................................................. 13 2.4. Histamin-4-Rezeptor ......................................................................................................... 16 2.4.1. Vorkommen und Funktion ............................................................................................. 16 2.5. TRP-Ionenkanäle ............................................................................................................... 18 2.5.1. Vorkommen, Funktion und Wirkmechanismen ............................................................. 20 2.5.1.1. Beteiligung am Juckreizgeschehen ............................................................................. 21 2.5.2. TRPV1-Kanal ................................................................................................................. 24 2.5.3. TRPA1-Kanal ................................................................................................................. 25 2.6. Juckreizmodelle in der Tiermedizin .................................................................................. 27 2.6.1. Einflüsse auf die Juckreizantwort im Mausmodell ........................................................ 29 2.6.1.1. Mausstämme ................................................................................................................ 29 2.6.1.2. Geschlecht ................................................................................................................... 30 2.6.1.3. Alter ............................................................................................................................. 31 2.6.1.4. Äußere Einflüsse ......................................................................................................... 31 3. Material und Methoden ..................................................................................................... 33 3.1. Material, Geräte und Tiere ................................................................................................ 33 IV Inhaltsverzeichnis 3.1.1. Material für In-vivo-Versuche ........................................................................................ 33 3.1.1.1 Agonisten ..................................................................................................................... 33 3.1.1.2. Antagonisten/Inhibitoren ............................................................................................. 34 3.1.2. RT-PCR Genotypisierung .............................................................................................. 34 3.1.3. Material für die Zellkultur .............................................................................................. 35 3.1.4. Material für Ca2+-Influx-Messungen .............................................................................. 36 3.1.5. Allgemeine Materialien/Verbrauchsmaterialien ............................................................ 36 3.1.6. Puffer und Lösungen ...................................................................................................... 38 3.1.7. Versuchstiere .................................................................................................................. 39 3.2. Versuchsübersicht ............................................................................................................. 41 3.3. In-vivo-Versuche ............................................................................................................... 42 3.3.1. Bewertung des Kratzverhaltens ...................................................................................... 43 3.3.2. Versuche zum Kratzverhalten nach 4-Methylhistamin-Injektion bei verschiedenen Mausstämmen ........................................................................................................................... 43 3.3.3. In-vivo-Untersuchungen zur Transmission des histamininduzierten Juckreizsignals .... 44 3.3.3.1. Dosis-Wirkungs-Untersuchungen ............................................................................... 44 3.3.3.2. Einfluss von TRP-Kanal-Inhibitoren auf histamininduzierten Juckreiz ..................... 44 3.3.3.3. Einfluss von Phospholipase-Inhibitoren auf histamininduzierten Juckreiz ................ 45 3.3.3.4. Einfluss von Proteinkinase-Inhibitoren auf histamininduzierten Juckreiz .................. 46 3.3.3.5. Einfluss eines Adenylylzyklase-Inhibitors auf histamininduzierten Juckreiz ............. 46 3.3.3.6. Untersuchungen an TRPV1- und TRPA1-Knockout-Mäuse ...................................... 47 3.3.3.6.1. Genotypisierung der TRPV1- und TRPA1-Knockout-Mäusen ................................ 47 3.3.3.7. Einfluss von ZNS- und nicht-ZNS-gängigen Histamin-4-Rezeptor-Antagonisten auf histamininduzierten Juckreiz .................................................................................................... 50 3.4. In-vitro-Untersuchungen ................................................................................................... 50 3.4.1. Funktionelle Untersuchungen an Spinalganglienneuronen zur Transmission des Juckreizsignals mittels Ca2+-Influx-Messungen ....................................................................... 50 3.4.1.1 Isolierung und Kultivierung von murinen Spinalganglienneuronen ............................ 50 3.4.1.2. Ca2+-Influx-Messungen an Spinalganglienneuronen .................................................. 51 3.4.1.2.1. Auswertung der Ca2+-Influx-Messungen ................................................................. 53 3.4.2. In-vitro-Versuche zum Vergleich der Rezeptorexpression auf Spinalganglien bei verschiedenen Mausstämmen ................................................................................................... 54 V Inhaltsverzeichnis 3.4.2.1. Funktionelle Rezeptoruntersuchungen an murinen Spinalganglienneuronen verschiedener Mausstämme mittels Ca2+-Influx Messungen ................................................... 54 3.5. Statistische Auswertung .................................................................................................... 55 4. Ergebnisse ........................................................................................................................... 56 4.1. In-vivo-Versuche ............................................................................................................... 56 4.1.1. Kratzverhalten nach intradermaler 4-Methylhistamin-Injektion bei vier unterschiedlichen Mausstämmen ............................................................................................. 56 4.1.2. Dosis-Wirkungsbeziehung verschiedener Histaminrezeptor-Agonisten bei CD-1- Mäusen ....................................................................................................................................
Load more

Recommended publications
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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
    [Show full text]
  • 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).
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • The Histamine H 3 Receptor: from Gene Cloning to H 3 Receptor Drugs
    REVIEWS THE HISTAMINE H3 RECEPTOR: FROM GENE CLONING TO H3 RECEPTOR DRUGS Rob Leurs, Remko A. Bakker, Henk Timmerman and Iwan J. P. de Esch Abstract | Since the cloning of the histamine H3 receptor cDNA in 1999 by Lovenberg and co-workers, this histamine receptor has gained the interest of many pharmaceutical companies as a potential drug target for the treatment of various important disorders, including obesity, attention-deficit hyperactivity disorder, Alzheimer’s disease, schizophrenia, as well as for myocardial ischaemia, migraine and inflammatory diseases. Here, we discuss relevant information on this target protein and describe the development of various H3 receptor agonists and antagonists, and their effects in preclinical animal models. The therapeutic modulation of several actions of the the periphery (mainly, but not exclusively, on neurons), biogenic amine histamine has proved to be medically the CNS contains the great majority of H3 receptors effective and also financially profitable for the pharma- (REFS 5–7).In rodents, H3 receptor expression is observed ceutical industry. Antagonists that target the histamine in, for example, the cerebral cortex, hippocampal forma- H1 receptor or the H2 receptor,which are used in the tion, amygdala, nucleus accumbens, globus pallidus, treatment of allergic conditions such as allergic rhinitis striatum and hypothalamus by autoradiography8, and gastric-acid-related disorders, respectively, have immunohistochemistry9 or in situ hybridization5,6. 1 been ‘blockbuster’ drugs for many years .Recently, H3 receptor expression is not confined to histamin- following the completion of the Human Genome ergic neurons, and, as a heteroreceptor, the H3 receptor is Project, the family of histamine receptors has been known to modulate various neurotransmitter systems in extended to include four different G-protein-coupled the brain.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0209331 A1 Arnou (43) Pub
    US 20150209331A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0209331 A1 Arnou (43) Pub. Date: Jul. 30, 2015 (54) HISTAMINE BALANCE RESTORATION on Aug. 20, 2013, provisional application No. 62/002, METHODS 613, filed on May 23, 2014. (71) Applicant: BioHealthonomics Inc., Santa Monica, Publication Classification CA (US) (51) Int. Cl. (72) Inventor: Cristian Arnou, Santa Monica, CA (US) A613 L/47 (2006.01) A6II 45/06 (2006.01) (21) Appl. No.: 14/684,174 (52) U.S. Cl. CPC ............... A61K 31/417 (2013.01); A61K 45/06 Related U.S. Application Data (57) ABSTRACT (63) Continuation of application No. 14/315,206, filed O Several embodiments provided herein relate to histamine Jun. 25, 2014, now Pat. No. 9,023,881, which is a dosing regimens are and uses of Such regimens in the resto continuation-in-part of application No. PCT/US2013/ ration of histamine balance in Subjects Suffering from, for 046420, filed on Jun. 18, 2013. example, histapenia and/or histadelia. Several embodiments (60) Provisional application No. 61/733,630, filed on Dec. also relate to the use of histamine dosing regimens for the 5, 2012, provisional application No. 61/867,966, filed treatment and/or prevention of migraine headaches. Patent Application Publication Jul. 30, 2015 Sheet 1 of 7 US 2015/0209331 A1 HN NH2 Figure 1 Patent Application Publication US 2015/0209331 A1 '9?02UOBUJOS SduJeJOGae) Patent Application Publication Jul. 30, 2015 Sheet 3 of 7 US 2015/0209331 A1 Extracellular Intracellular PLC AC 4 N . PKC Ca PKA Biological Effects Figure 3 Patent Application Publication Jul.
    [Show full text]
  • Product Data Sheet
    Inhibitors Product Data Sheet VUF10460 • Agonists Cat. No.: HY-101420 CAS No.: 1028327-66-3 Molecular Formula: C₁₅H₁₉N₅ • Molecular Weight: 269.34 Screening Libraries Target: Histamine Receptor Pathway: GPCR/G Protein; Immunology/Inflammation; Neuronal Signaling Storage: Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month SOLVENT & SOLUBILITY In Vitro DMSO : ≥ 36 mg/mL (133.66 mM) * "≥" means soluble, but saturation unknown. Mass Solvent 1 mg 5 mg 10 mg Concentration Preparing 1 mM 3.7128 mL 18.5639 mL 37.1278 mL Stock Solutions 5 mM 0.7426 mL 3.7128 mL 7.4256 mL 10 mM 0.3713 mL 1.8564 mL 3.7128 mL Please refer to the solubility information to select the appropriate solvent. BIOLOGICAL ACTIVITY Description VUF10460 is a non-imidazole histamine H4 receptor agonist; binds to rat H4 receptor with a pKi of 7.46. IC₅₀ & Target pKi: 7.46 (H4)[1] In Vitro UF10460 binds to rat H3 and H4 receptor with pKi values of 5.75, and 7.46, respectively. VUF10460 displays approximately a 50-fold selectivity for the rat H4 receptor over the H3 receptor[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo HCl-induced rat gastric lesions is significantly enhanced by the H4 receptor agonists VUF10460. This effect is not modified by H4 receptor antagonist JNJ7777120[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Page 1 of 2 www.MedChemExpress.com PROTOCOL Animal Rats: VUF10460 is dissolved in 100% DMSO.
    [Show full text]
  • Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives As Potential Molecular Targets
    biomolecules Review Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets Phuong Linh Nguyen and Jungsook Cho * College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Gyeonggi 10326, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-31-961-5211 Abstract: High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine and its cognate receptors in cancer biology. We also discuss the novel therapeutic approaches of selective HR ligands and their potential prognostic values in cancer treatment. Briefly, histamine is highly implicated in cancer development, growth, and metastasis through interactions with distinct HRs. It also regulates the infiltration of immune cells into the tumor sites, exerting an immunomodulatory function. Moreover, the effects of various HR ligands, including H1R antagonists, H2R antagonists, and H4R agonists, on tumor progression in many different cancer types are described. Interestingly, the expression levels of HR subtypes may serve as prognostic biomarkers in several cancers. Taken together, HRs are promising targets for cancer treatment, and HR ligands may offer novel therapeutic potential, alone or in combination with Citation: Nguyen, P.L.; Cho, J. conventional therapy. However, due to the complexity of the pathophysiological roles of histamine Pathophysiological Roles of Histamine Receptors in Cancer and HRs in cancer biology, further studies are warranted before HR ligands can be introduced into Progression: Implications and clinical settings.
    [Show full text]