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Characterisation of the Α1b-Adrenoceptor by Modeling, Dynamics and Virtual Screening Kapil Jain B.Pharm, M.S.(Pharm.)
Characterisation of the α1B-Adrenoceptor by Modeling, Dynamics and Virtual Screening Kapil Jain B.Pharm, M.S.(Pharm.) A Thesis submitted for the degree of Master of Philosophy at The University of Queensland in 2018 Institute for Molecular Bioscience 0 Abstract G protein-coupled receptors (GPCRs) are the largest druggable class of proteins yet relatively little is known about the mechanism by which agonist binding induces the conformational changes necessary for G protein activation and intracellular signaling. Recently, the Kobilka group has shown that agonists, neutral antagonists and inverse agonists stabilise distinct extracellular surface (ECS) conformations of the β2-adrenergic receptor (AR) opening up new possibilities for allosteric drug targeting at GPCRs. The goal of this project is to extend these studies to define how the ECS conformation of the α1B-AR changes during agonist binding and develop an understanding of ligand entry and exit mechanisms that may help in the design of specific ligands with higher selectivity, efficacy and longer duration of action. Two parallel approaches were initiated to identify likely functional residues. The role of residues lining the primary binding site were predicted by online web server (Q-Site Finder) while secondary binding sites residues were predicted from molecular dynamics (MD) simulations. Predicted functionally significant residues were mutated and their function was established using FLIPR, radioligand and saturation binding assays. Despite the α1B-AR being pursued as a drug target for over last few decades, few specific agonists and antagonists are known to date. In an attempt to address this gap, we pursued ligand-based approach to find potential new leads. -
(12) United States Patent (10) Patent No.: US 9,498,481 B2 Rao Et Al
USOO9498481 B2 (12) United States Patent (10) Patent No.: US 9,498,481 B2 Rao et al. (45) Date of Patent: *Nov. 22, 2016 (54) CYCLOPROPYL MODULATORS OF P2Y12 WO WO95/26325 10, 1995 RECEPTOR WO WO99/O5142 2, 1999 WO WOOO/34283 6, 2000 WO WO O1/92262 12/2001 (71) Applicant: Apharaceuticals. Inc., La WO WO O1/922.63 12/2001 olla, CA (US) WO WO 2011/O17108 2, 2011 (72) Inventors: Tadimeti Rao, San Diego, CA (US); Chengzhi Zhang, San Diego, CA (US) OTHER PUBLICATIONS Drugs of the Future 32(10), 845-853 (2007).* (73) Assignee: Auspex Pharmaceuticals, Inc., LaJolla, Tantry et al. in Expert Opin. Invest. Drugs (2007) 16(2):225-229.* CA (US) Wallentin et al. in the New England Journal of Medicine, 361 (11), 1045-1057 (2009).* (*) Notice: Subject to any disclaimer, the term of this Husted et al. in The European Heart Journal 27, 1038-1047 (2006).* patent is extended or adjusted under 35 Auspex in www.businesswire.com/news/home/20081023005201/ U.S.C. 154(b) by Od en/Auspex-Pharmaceuticals-Announces-Positive-Results-Clinical M YW- (b) by ayS. Study (published: Oct. 23, 2008).* This patent is Subject to a terminal dis- Concert In www.concertpharma. com/news/ claimer ConcertPresentsPreclinicalResultsNAMS.htm (published: Sep. 25. 2008).* Concert2 in Expert Rev. Anti Infect. Ther. 6(6), 782 (2008).* (21) Appl. No.: 14/977,056 Springthorpe et al. in Bioorganic & Medicinal Chemistry Letters 17. 6013-6018 (2007).* (22) Filed: Dec. 21, 2015 Leis et al. in Current Organic Chemistry 2, 131-144 (1998).* Angiolillo et al., Pharmacology of emerging novel platelet inhibi (65) Prior Publication Data tors, American Heart Journal, 2008, 156(2) Supp. -
Functional Selectivity and Partial Efficacy at the Monoamine Transporters: a Unified Model of Allosteric Modulation and Amphetamine-Induced Substrate Release
1521-0111/95/3/303–312$35.00 https://doi.org/10.1124/mol.118.114793 MOLECULAR PHARMACOLOGY Mol Pharmacol 95:303–312, March 2019 Copyright ª 2019 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. MINIREVIEW Functional Selectivity and Partial Efficacy at the Monoamine Transporters: A Unified Model of Allosteric Modulation and Amphetamine-Induced Substrate Release Peter S. Hasenhuetl,1,2 Shreyas Bhat,2 Michael Freissmuth, and Walter Sandtner Downloaded from Institute of Pharmacology, Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria Received October 2, 2018; accepted December 13, 2018 ABSTRACT molpharm.aspetjournals.org All clinically approved drugs targeting the plasmalemmal trans- allosteric inhibition and stimulation of MATs, which can be porters for dopamine, norepinephrine, and serotonin act either functionally selective for either substrate uptake or amphetamine- as competitive uptake inhibitors or as amphetamine-like releas- induced release. These concepts are integrated into a parsimonious ers. Monoamine transporter (MAT) ligands that allosterically kinetic framework, which relies exclusively on physiologic transport affect MAT-mediated substrate uptake, release, or both were modes (without any deviation from an alternating access mecha- recently discovered. Their modes of action have not yet been nism). The model posits cooperative substrate and Na1 binding and explained in a unified framework. Here, we go beyond compet- functional selectivity by conformational selection (i.e., preference of itive inhibitors and classic amphetamines and introduce con- the allosteric modulators for the substrate-loaded or substrate-free cepts for partial efficacy at and allosteric modulation of MATs. -
Ageing, Sex and Cardioprotection Marisol Ruiz-Meana1,2, Kerstin Boengler3, David Garcia-Dorado1,2, Derek J
Kaambre Tuuli (Orcid ID: 0000-0001-5755-4694) Kararigas Georgios (Orcid ID: 0000-0002-8187-0176) Ageing, sex and cardioprotection Marisol Ruiz-Meana1,2, Kerstin Boengler3, David Garcia-Dorado1,2, Derek J. Hausenloy4,5,6,7,8,9, Tuuli Kaambre10, Georgios Kararigas11,12, Cinzia Perrino13, Rainer Schulz3, Kirsti Ytrehus14. 1 Hospital Universitari Vall d’Hebron, Department of Cardiology. Vall d’Hebron Institut de Recerca (VHIR).Universitat Autonoma de Barcelona, Spain. 2 Centro de Investigación Biomédica en Red-CV, CIBER-CV, Spain. 3Institute of Physiology, Justus-Liebig University Giessen. Giessen 35392, Aulweg 129, Germany. 4Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore. 5National Heart Research Institute Singapore, National Heart Centre, Singapore. 6Yong Loo Lin School of Medicine, National University Singapore, Singapore. 7The Hatter Cardiovascular Institute, University College London, London, UK. 8The National Institute of Health Research University College London Hospitals Biomedical Research Centre, Research & Development, London, UK. 9Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Nuevo Leon, Mexico. 10Laboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia. 11Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. 12DZHK (German Centre for Cardiovascular Research), partner site Berlin, -
M100907, a Serotonin 5-HT2A Receptor Antagonist and Putative Antipsychotic, Blocks Dizocilpine-Induced Prepulse Inhibition Defic
M100907, a Serotonin 5-HT2A Receptor Antagonist and Putative Antipsychotic, Blocks Dizocilpine-Induced Prepulse Inhibition Deficits in Sprague–Dawley and Wistar Rats Geoffrey B. Varty, Ph.D., Vaishali P. Bakshi, Ph.D., and Mark A. Geyer, Ph.D. a In a recent study using Wistar rats, the serotonergic 5-HT2 1 receptor agonist cirazoline disrupts PPI. As risperidone a receptor antagonists ketanserin and risperidone reduced the and M100907 have affinity at the 1 receptor, a final study disruptive effects of the noncompetitive N-methyl-D- examined whether M100907 would block the effects of aspartate (NMDA) antagonist dizocilpine on prepulse cirazoline on PPI. Risperidone partially, but inhibition (PPI), suggesting that there is an interaction nonsignificantly, reduced the effects of dizocilpine in Wistar between serotonin and glutamate in the modulation of PPI. rats, although this effect was smaller than previously In contrast, studies using the noncompetitive NMDA reported. Consistent with previous studies, risperidone did antagonist phencyclidine (PCP) in Sprague–Dawley rats not alter the effects of dizocilpine in Sprague–Dawley rats. found no effect with 5-HT2 antagonists. To test the hypothesis Most importantly, M100907 pretreatment fully blocked the that strain differences might explain the discrepancy in effect of dizocilpine in both strains; whereas SDZ SER 082 these findings, risperidone was tested for its ability to had no effect. M100907 had no influence on PPI by itself reduce the PPI-disruptive effects of dizocilpine in Wistar and did not reduce the effects of cirazoline on PPI. These and Sprague–Dawley rats. Furthermore, to determine studies confirm the suggestion that serotonin and glutamate which serotonergic receptor subtype may mediate this effect, interact in modulating PPI and indicate that the 5-HT2A the 5-HT2A receptor antagonist M100907 (formerly MDL receptor subtype mediates this interaction. -
4 Supplementary File
Supplemental Material for High-throughput screening discovers anti-fibrotic properties of Haloperidol by hindering myofibroblast activation Michael Rehman1, Simone Vodret1, Luca Braga2, Corrado Guarnaccia3, Fulvio Celsi4, Giulia Rossetti5, Valentina Martinelli2, Tiziana Battini1, Carlin Long2, Kristina Vukusic1, Tea Kocijan1, Chiara Collesi2,6, Nadja Ring1, Natasa Skoko3, Mauro Giacca2,6, Giannino Del Sal7,8, Marco Confalonieri6, Marcello Raspa9, Alessandro Marcello10, Michael P. Myers11, Sergio Crovella3, Paolo Carloni5, Serena Zacchigna1,6 1Cardiovascular Biology, 2Molecular Medicine, 3Biotechnology Development, 10Molecular Virology, and 11Protein Networks Laboratories, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 34149, Trieste, Italy 4Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy 5Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany 6Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy 7National Laboratory CIB, Area Science Park Padriciano, Trieste, 34149, Italy 8Department of Life Sciences, University of Trieste, Trieste, 34127, Italy 9Consiglio Nazionale delle Ricerche (IBCN), CNR-Campus International Development (EMMA- INFRAFRONTIER-IMPC), Rome, Italy This PDF file includes: Supplementary Methods Supplementary References Supplementary Figures with legends 1 – 18 Supplementary Tables with legends 1 – 5 Supplementary Movie legends 1, 2 Supplementary Methods Cell culture Primary murine fibroblasts were isolated from skin, lung, kidney and hearts of adult CD1, C57BL/6 or aSMA-RFP/COLL-EGFP mice (1) by mechanical and enzymatic tissue digestion. Briefly, tissue was chopped in small chunks that were digested using a mixture of enzymes (Miltenyi Biotec, 130- 098-305) for 1 hour at 37°C with mechanical dissociation followed by filtration through a 70 µm cell strainer and centrifugation. -
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. -
Full-Text PDF (Final Published Version)
Alexander, S. P. H., Cidlowski, J. A., Kelly, E., Marrion, N. V., Peters, J. A., Faccenda, E., Harding, S. D., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A., & CGTP Collaborators (2017). THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Nuclear hormone receptors. British Journal of Pharmacology, 174, S208-S224. https://doi.org/10.1111/bph.13880 Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1111/bph.13880 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Wiley at https://doi.org/10.1111/bph.13880 . Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2017/18: Nuclear hormone receptors. British Journal of Pharmacology (2017) 174, S208–S224 THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Nuclear hormone receptors Stephen PH Alexander1, John A Cidlowski2, Eamonn Kelly3, Neil V Marrion3, John A Peters4, Elena Faccenda5, Simon D Harding5,AdamJPawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical -
6. Literaturverzeichnis 6
Seite 148 6. Literaturverzeichnis 6. Literaturverzeichnis Aboud R., Shafii M. & Docherty J.R. (1993). Investigation of the subtypes of α1-adrenoceptor mediating contractions of rat aorta, vas deferens and spleen. Br. J. Pharmacol., 109, 80-87. Aghajanian G.K. & Marek G.J. (1999). Serotonin and hallucinogens. Neuropsychopharmacology, 21 (Suppl.), 16S-23S. Ahlquist R.P. (1948). A study of the adrenergic receptors. Am. J. Physiol.. 153, 585-600. Akin D. & Gurdal H. (2002). Involvement of 5-HT1B and 5-HT1D receptors in sumatriptan mediated vasocontractile response in rabbit common carotid artery. Br. J. Pharmacol., 136, 177-182. Ali A., Cheng H.Y., Ting K.N. & Wilson V.G. (1998). Rilmenidine reveals differences in the pharmacological characteristics of prejunctional α2-adrenoceptors in the guinea-pig, rat and pig. Br. J. Pharmacol., 125, 127-135. Almaula N., Ebersole B.J., Ballesteros J.A., Weinstein H. & Sealfon S.C. (1996a). Contribution of a helix 5 locus to selectivity of hallucinogenic and nonhallucinogenic ligands for the human 5-hydroxytryptamine2A and 5- hydroxytryptamine2C receptors: direct and indirect effects on ligand affinity mediated by the same locus. Mol. Pharmacol., 50, 34-42. Almaula N., Ebersole B.J., Zhang D., Weinstein H. & Sealfon S.C. (1996b). Mapping the binding site pocket of the 3.36(159) serotonin 5-Hydroxytryptamine2A receptor. Ser provides a second interaction site for the protonated amine of serotonin but not of lysergic acid diethylamide or bufotenin. J. Biol. Chem., 271, 14672-14675. Amobi N., Guillebaud J., Coker C., Mulvin D. & Smith I.C.H. (1999). Functional characterization of α1-adrenoceptor subtypes in longitudinal and circular muscle of human vas deferens. -
Insights Into Nuclear G-Protein-Coupled Receptors As Therapeutic Targets in Non-Communicable Diseases
pharmaceuticals Review Insights into Nuclear G-Protein-Coupled Receptors as Therapeutic Targets in Non-Communicable Diseases Salomé Gonçalves-Monteiro 1,2, Rita Ribeiro-Oliveira 1,2, Maria Sofia Vieira-Rocha 1,2, Martin Vojtek 1,2 , Joana B. Sousa 1,2,* and Carmen Diniz 1,2,* 1 Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; [email protected] (S.G.-M.); [email protected] (R.R.-O.); [email protected] (M.S.V.-R.); [email protected] (M.V.) 2 LAQV/REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal * Correspondence: [email protected] (J.B.S.); [email protected] (C.D.) Abstract: G-protein-coupled receptors (GPCRs) comprise a large protein superfamily divided into six classes, rhodopsin-like (A), secretin receptor family (B), metabotropic glutamate (C), fungal mating pheromone receptors (D), cyclic AMP receptors (E) and frizzled (F). Until recently, GPCRs signaling was thought to emanate exclusively from the plasma membrane as a response to extracellular stimuli but several studies have challenged this view demonstrating that GPCRs can be present in intracellular localizations, including in the nuclei. A renewed interest in GPCR receptors’ superfamily emerged and intensive research occurred over recent decades, particularly regarding class A GPCRs, but some class B and C have also been explored. Nuclear GPCRs proved to be functional and capable of triggering identical and/or distinct signaling pathways associated with their counterparts on the cell surface bringing new insights into the relevance of nuclear GPCRs and highlighting the Citation: Gonçalves-Monteiro, S.; nucleus as an autonomous signaling organelle (triggered by GPCRs). -
Fluticasone Furoate and Vilanterol for the Treatment of Chronic Obstructive Pulmonary Disease
Expert Review of Respiratory Medicine ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20 Fluticasone furoate and vilanterol for the treatment of chronic obstructive pulmonary disease Gaetano Caramori, Paolo Ruggeri, Paolo Casolari, Kian Fan Chung, Giuseppe Girbino & Ian M. Adcock To cite this article: Gaetano Caramori, Paolo Ruggeri, Paolo Casolari, Kian Fan Chung, Giuseppe Girbino & Ian M. Adcock (2017): Fluticasone furoate and vilanterol for the treatment of chronic obstructive pulmonary disease, Expert Review of Respiratory Medicine, DOI: 10.1080/17476348.2017.1386564 To link to this article: http://dx.doi.org/10.1080/17476348.2017.1386564 Accepted author version posted online: 28 Sep 2017. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierx20 Download by: [Imperial College London Library] Date: 29 September 2017, At: 01:13 Publisher: Taylor & Francis Journal: Expert Review of Respiratory Medicine DOI: 10.1080/17476348.2017.1386564 Review Fluticasone furoate and vilanterol for the treatment of chronic obstructive pulmonary disease Gaetano Caramori1*, Paolo Ruggeri1, Paolo Casolari2, Kian Fan Chung3, Giuseppe Girbino1, Ian M. Adcock3. 1Unità Operativa Complessa di Pneumologia, Dipartimento di Scienze Biomediche, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF) Università degli Studi di Messina, Italy. 2Centro Interdipartimentale per lo Studio delle Malattie Infiammatorie delle Vie Aeree e Patologie Fumo-correlate (CEMICEF; formerly Centro di Ricerca su Asma e BPCO), Sezione di Medicina Interna e Cardiorespiratoria, Università di Ferrara, Ferrara, Italy. 3Airways Disease Section, National Heart and Lung Institute, Royal Brompton Hospital Biomedical Research Unit, Imperial College London, UK. -
Clozapine and Olanzapine, but Not Haloperidol, Suppress Serotonin Efflux in the Medial Prefrontal Cortex Elicited by Phencyclidi
ARTICLE International Journal of Neuropsychopharmacology (2006), 9, 565–573. Copyright f 2005 CINP doi:10.1017/S1461145705005900 Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine Merce` Amargo´s-Bosch, Xavier Lo´pez-Gil, Francesc Artigas and Albert Adell Department of Neurochemistry, Institut d’Investigacions Biome`diques de Barcelona, CSIC (IDIBAPS), 08036 Barcelona, Spain Abstract N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) and ketamine can evoke psychotic symptoms in normal individuals and schizophrenic patients. Here, we have examined the effects of PCP (5 mg/kg) and ketamine (25 mg/kg) on the efflux of serotonin (5-HT) in the medial pre- frontal cortex (mPFC) and their possible blockade by the antipsychotics, clozapine, olanzapine and halo- peridol, as well as ritanserin (5-HT2A/2C receptor antagonist) and prazosin (a1-adrenoceptor antagonist). The systemic administration, but not the local perfusion, of the two NMDA receptor antagonists markedly increased the efflux of 5-HT in the mPFC. The atypical antipsychotics clozapine (1 mg/kg) and olanzapine (1 mg/kg), and prazosin (0.3 mg/kg), but not the classical antipsychotic haloperidol (1 mg/kg), reversed the PCP- and ketamine-induced increase in 5-HT efflux. Ritanserin (5 mg/kg) was able to reverse only the effect of PCP. These findings indicate that an increased serotonergic transmission in the mPFC is a functional consequence of NMDA receptor hypofunction and this effect is blocked by atypical antipsychotic drugs. Received 24 March 2005; Reviewed 18 April 2005; Revised 15 June 2005; Accepted 15 June 2005; First published online 15 August 2005 Key words: Clozapine, haloperidol, ketamine, phencyclidine, serotonin.