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SYNTHESIS and STRUCTURE ACTIVITY STUDIES of NOVEL H3-RECEPTOR HISTAMINE ANTAGONISTS. a Thesis Presented in Partial Fulfilment Of
1 SYNTHESIS AND STRUCTURE ACTIVITY STUDIES OF NOVEL H3-RECEPTOR HISTAMINE ANTAGONISTS. A thesis presented in partial fulfilment of the requirements for the Doctor of Philosophy Degree of the University of London SEYED KIUMARS HOSSEINI Department of Chemistry University College London September 1991 Attention is drawn to the fact that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that the copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without prior consent of the author. Signature: Date..^*^^~ ProQuest Number: 10609847 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10609847 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 2 Acknowledgements I would like to express my gratitude for the guidance and generous support of Prof. C. R. Ganellin and for the financial support of Bioproject in association with Centre Paul Broca de rinserm, Paris. Thanks to Prof. -
WO 2015/179249 Al 26 November 2015 (26.11.2015) P O P C T
(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 WO 2015/179249 Al 26 November 2015 (26.11.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/11 (2006.01) A61K 38/08 (2006.01) kind of national protection available): AE, AG, AL, AM, C12N 15/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2015/031213 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 15 May 2015 (15.05.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/000,43 1 19 May 2014 (19.05.2014) US kind of regional protection available): ARIPO (BW, GH, 62/129,746 6 March 2015 (06.03.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (72) Inventors; and TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicants : GELLER, Bruce, L. -
Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications
International Journal of Molecular Sciences Review Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications Daniel Fernández-Villa 1, Maria Rosa Aguilar 1,2 and Luis Rojo 1,2,* 1 Instituto de Ciencia y Tecnología de Polímeros, Consejo Superior de Investigaciones Científicas, CSIC, 28006 Madrid, Spain; [email protected] (D.F.-V.); [email protected] (M.R.A.) 2 Consorcio Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina, 28029 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-915-622-900 Received: 18 September 2019; Accepted: 7 October 2019; Published: 9 October 2019 Abstract: Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications. Keywords: folic acid antagonists; antifolates; antibiotics; antibacterials; immunomodulation; sulfonamides; antimalarial 1. -
Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation
www.sciencemag.org/cgi/content/full/327/5963/348/DC1 Supporting Online Material for Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation Jason Rihel,* David A. Prober, Anthony Arvanites, Kelvin Lam, Steven Zimmerman, Sumin Jang, Stephen J. Haggarty, David Kokel, Lee L. Rubin, Randall T. Peterson, Alexander F. Schier* *To whom correspondence should be addressed. E-mail: [email protected] (A.F.S.); [email protected] (J.R.) Published 15 January 2010, Science 327, 348 (2010) DOI: 10.1126/science.1183090 This PDF file includes: Materials and Methods SOM Text Figs. S1 to S18 Table S1 References Supporting Online Material Table of Contents Materials and Methods, pages 2-4 Supplemental Text 1-7, pages 5-10 Text 1. Psychotropic Drug Discovery, page 5 Text 2. Dose, pages 5-6 Text 3. Therapeutic Classes of Drugs Induce Correlated Behaviors, page 6 Text 4. Polypharmacology, pages 6-7 Text 5. Pharmacological Conservation, pages 7-9 Text 6. Non-overlapping Regulation of Rest/Wake States, page 9 Text 7. High Throughput Behavioral Screening in Practice, page 10 Supplemental Figure Legends, pages 11-14 Figure S1. Expanded hierarchical clustering analysis, pages 15-18 Figure S2. Hierarchical and k-means clustering yield similar cluster architectures, page 19 Figure S3. Expanded k-means clustergram, pages 20-23 Figure S4. Behavioral fingerprints are stable across a range of doses, page 24 Figure S5. Compounds that share biological targets have highly correlated behavioral fingerprints, page 25 Figure S6. Examples of compounds that share biological targets and/or structural similarity that give similar behavioral profiles, page 26 Figure S7. -
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. -
PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. -
Drug Delivery Systems on Leprosy Therapy: Moving Towards Eradication?
pharmaceutics Review Drug Delivery Systems on Leprosy Therapy: Moving Towards Eradication? Luíse L. Chaves 1,2,*, Yuri Patriota 2, José L. Soares-Sobrinho 2 , Alexandre C. C. Vieira 1,3, Sofia A. Costa Lima 1,4 and Salette Reis 1,* 1 Laboratório Associado para a Química Verde, Rede de Química e Tecnologia, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal; [email protected] (A.C.C.V.); slima@ff.up.pt (S.A.C.L.) 2 Núcleo de Controle de Qualidade de Medicamentos e Correlatos, Universidade Federal de Pernambuco, Recife 50740-521, Brazil; [email protected] (Y.P.); [email protected] (J.L.S.-S.) 3 Laboratório de Tecnologia dos Medicamentos, Universidade Federal de Pernambuco, Recife 50740-521, Brazil 4 Cooperativa de Ensino Superior Politécnico e Universitário, Instituto Universitário de Ciências da Saúde, 4585-116 Gandra, Portugal * Correspondence: [email protected] (L.L.C.); shreis@ff.up.pt (S.R.) Received: 30 October 2020; Accepted: 4 December 2020; Published: 11 December 2020 Abstract: Leprosy disease remains an important public health issue as it is still endemic in several countries. Mycobacterium leprae, the causative agent of leprosy, presents tropism for cells of the reticuloendothelial and peripheral nervous system. Current multidrug therapy consists of clofazimine, dapsone and rifampicin. Despite significant improvements in leprosy treatment, in most programs, successful completion of the therapy is still sub-optimal. Drug resistance has emerged in some countries. This review discusses the status of leprosy disease worldwide, providing information regarding infectious agents, clinical manifestations, diagnosis, actual treatment and future perspectives and strategies on targets for an efficient targeted delivery therapy. -
In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs As Inverse H1 Receptor Agonists
0022-3565/07/3221-172–179$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 322, No. 1 Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics 118869/3215703 JPET 322:172–179, 2007 Printed in U.S.A. In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs as Inverse H1 Receptor Agonists R. A. Bakker,1 M. W. Nicholas,2 T. T. Smith, E. S. Burstein, U. Hacksell, H. Timmerman, R. Leurs, M. R. Brann, and D. M. Weiner Department of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.A.B., H.T., R.L.); ACADIA Pharmaceuticals Inc., San Diego, California (R.A.B., M.W.N., T.T.S., E.S.B., U.H., M.R.B., D.M.W.); and Departments of Pharmacology (M.R.B.), Neurosciences (D.M.W.), and Psychiatry (D.M.W.), University of California, San Diego, California Received January 2, 2007; accepted March 30, 2007 Downloaded from ABSTRACT The human histamine H1 receptor (H1R) is a prototypical G on this screen, we have reported on the identification of 8R- protein-coupled receptor and an important, well characterized lisuride as a potent stereospecific partial H1R agonist (Mol target for the development of antagonists to treat allergic con- Pharmacol 65:538–549, 2004). In contrast, herein we report on jpet.aspetjournals.org ditions. Many neuropsychiatric drugs are also known to po- a large number of varied clinical and chemical classes of drugs tently antagonize this receptor, underlying aspects of their side that are active in the central nervous system that display potent effect profiles. -
Food Sample Preparation for the Determination of Sulfonamides by High-Performance Liquid Chromatography: State-Of-The-Art
separations Review Food Sample Preparation for the Determination of Sulfonamides by High-Performance Liquid Chromatography: State-of-the-Art Dimitrios Bitas 1, Abuzar Kabir 2 ID , Marcello Locatelli 3 ID and Victoria Samanidou 1,* ID 1 Laboratory of Analytical Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; [email protected] 2 International Forensic Research Institute, Department of Chemistry and Biochemistry, Florida International University, 11200 SW 8th St, Miami, FL 33199, USA; akabir@fiu.edu 3 Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; [email protected] * Correspondence: [email protected]; Tel.: +30-231-099-7698 Received: 30 April 2018; Accepted: 28 May 2018; Published: 4 June 2018 Abstract: Antibiotics are a common practice in veterinary medicine, mainly for therapeutic purposes. Sectors of application include livestock farming, aquacultures, and bee-keeping, where bacterial infections are frequent and can be economically damaging. However, antibiotics are usually administered in sub-therapeutic doses as prophylactic and growth promoting agents. Due to their excessive use, antibiotic residues can be present in foods of animal origin, which include meat, fish, milk, eggs, and honey, posing health risks to consumers. For this reason, authorities have set maximum residue limits (MRLs) of certain antibiotics in food matrices, while analytical methods for their determination have been developed. This work focuses on antibiotic extraction and determination, part of which was presented at the “1st Conference in Chemistry for Graduate, Postgraduate Students and PhD Candidates at the Aristotle University of Thessaloniki”. Taking a step further, this paper is a review of the most recent sample preparation protocols applied for the extraction of sulfonamide antibiotics from food samples and their determination with high-performance liquid chromatography (HPLC), covering a five-year period. -
Mail Order Maintenance Medication Exclusion List
Maintenance Medication Exclusion List The following is a list of drugs that are excluded as maintenance medications. Medications which are listed here cannot be filled through the mail order pharmacy for the mail order incentive. This list includes both formulary/preferred and non-formulary/non-preferred medications, and does not provide information regarding the specific coverage, limitations, exclusions or quotas an individual member may have. Some dosage forms and strengths of a particular drug may be considered maintenance medications, whereas others may not. This list is sorted alphabetically by generic drug name. Generic drug names are written in lower case letters. Brand drug names (or some generic drugs with a trade name) are written in CAPITAL letters. Some drugs do not have a brand name available, in such cases the generic name is listed in the “Brand Name” column. This list of drugs should not be used to determine pharmacy benefits, such as prescription copay/coinsurance amounts or formulary status. If you have questions about the formulary status of a medication, or your prescription benefits, please call our Member Services Department at 1-888-681-7878 (toll free). For the hearing or speech impaired: 1-800-521-4874 (toll free TTY). The medications on this list are subject to change at any time. Exclusions: Any formulation that is required to be administered by a skilled medical professional or in a medical office, drugs infused in the home or in an infusion center, drugs that may have other quantity restrictions, any state law that may prohibit the mailing of certain dosage formulation of a drug, drugs that have a high potential for waste and diversion, drugs that require temperature control upon mailing and drugs that require refrigeration. -
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. -
EMA/CVMP/158366/2019 Committee for Medicinal Products for Veterinary Use
Ref. Ares(2019)6843167 - 05/11/2019 31 October 2019 EMA/CVMP/158366/2019 Committee for Medicinal Products for Veterinary Use Advice on implementing measures under Article 37(4) of Regulation (EU) 2019/6 on veterinary medicinal products – Criteria for the designation of antimicrobials to be reserved for treatment of certain infections in humans Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Introduction On 6 February 2019, the European Commission sent a request to the European Medicines Agency (EMA) for a report on the criteria for the designation of antimicrobials to be reserved for the treatment of certain infections in humans in order to preserve the efficacy of those antimicrobials. The Agency was requested to provide a report by 31 October 2019 containing recommendations to the Commission as to which criteria should be used to determine those antimicrobials to be reserved for treatment of certain infections in humans (this is also referred to as ‘criteria for designating antimicrobials for human use’, ‘restricting antimicrobials to human use’, or ‘reserved for human use only’). The Committee for Medicinal Products for Veterinary Use (CVMP) formed an expert group to prepare the scientific report. The group was composed of seven experts selected from the European network of experts, on the basis of recommendations from the national competent authorities, one expert nominated from European Food Safety Authority (EFSA), one expert nominated by European Centre for Disease Prevention and Control (ECDC), one expert with expertise on human infectious diseases, and two Agency staff members with expertise on development of antimicrobial resistance .