DOCSLIB.ORG

A Cell Protection Screen Reveals Potent Inhibitors of Multiple Stages of the Hepatitis C Virus Life Cycle

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Cell Protection Screen Reveals Potent Inhibitors of Multiple Stages of the Hepatitis C Virus Life Cycle A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle Karuppiah Chockalingama, Rudo L. Simeona, Charles M. Riceb, and Zhilei Chena,1 aArtie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX 77843; and bCenter for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065 Contributed by Charles M. Rice, December 30, 2009 (sent for review December 16, 2009) The hepatitis C virus (HCV) life cycle involves multiple steps, but against different aspects of the HCV life cycle. In particular, we most current drug candidates target only viral replication. The reasoned that n4mBid cells should be able to report the presence inability to systematically discover inhibitors targeting multiple of anti-HCV molecules via increased cell viability relative to steps of the HCV life cycle has hampered antiviral development. We untreated cells in the presence of HCV infection. Such an assay present a simple screen for HCV antivirals based on the alleviation should be simple, quick, cost-effective, and, importantly, should of HCV-mediated cytopathic effect in an engineered cell line— obviate the need for a separate assay to assess drug hits for cyto- n4mBid. This approach obviates the need for a secondary screen toxic effects because toxic drugs should not produce a positive cell to avoid cytotoxic false-positive hits. Application of our screen to viability readout. 1280 compounds, many in clinical trials or approved for therapeutic use, yielded >200 hits. Of the 55 leading hits, 47 inhibited one or Results and Discussion more aspects of the HCV life cycle by >40%. Six compounds blocked Viral Inhibitors Effectively Protect n4mBid Cells from HCV Infection. HCV entry to levels similar to an antibody (JS-81) targeting the HCV To verify that inhibition of different aspects of the HCV life cycle entry receptor CD81. Seven hits inhibited HCV replication and/or can alleviate the HCV-induced cytopathic effect experienced by infectious virus production by >100-fold, with one (quinidine) inhib- n4mBid cells, we tested the effect of known HCV replication, iting infectious virus production by 450-fold relative to HCV repli- entry, and assembly/release inhibitors on n4mBid cell viability in cation levels. This approach is simple and inexpensive and should the presence of HCV infection. N4mBid cells were seeded in 96- enable the rapid discovery of new classes of HCV life cycle inhibitors. well plates in the presence of both Jc1 HCVcc (14) and small molecules, and cell viability was quantified 4 days later (Fig. 1A). cell death | drug | high throughput | rescue | virus assembly For small-molecule cytotoxicity profiles, regular growth media was used in place of HCVcc. The HCV replication inhibitors VX-950 epatitis C virus (HCV) infection is a major public health (15), 2′-C-methyladenosine (2′CMA) (16), and cyclosporin A (17), Hproblem, putting ~180 million infected individuals worldwide targeting the NS3-4A protease, NS5B RNA-dependent RNA (3% of the world’s population) at risk for developing cirrhosis, polymerase, and a required cellular factor [cyclophilin A (18)], hepatocellular carcinoma, and liver failure. Chronic hepatitis C is respectively, each produced a strong dose-dependent increase in a leading cause for liver transplantation in the Western world. The n4mBid cell viability following HCV infection. A recombinant current standard IFN-based therapy is costly, time-consuming, monoclonal antibody (mAb JS-81) against the essential HCV entry riddled with serious side effects, and cures only ∼50% of patients factor CD81 (19) also exhibited a dose-dependent protection of infected with the most common genotype. Although it is antici- n4mBid cells from the HCV cytopathic effect, as did the HCV fi pated that small molecules that effectively inhibit the HCV life assembly/release-speci c inhibitor naringenin (20) and the cyto- α B cycle can complement or even replace IFN therapy, no anti-HCV kine IFN -2a (Fig. 1 ). drugs have yet been approved for human use. Efforts to develop HCV antivirals mostly target only viral replication due to wide- Library Screening for Antivirals Using n4mBid Cells. We next screened the LOPAC1280 library consisting of 1280 compounds spread dependence on the HCV replicon model (1–4), which known to be pharmacologically active in a variety of cellular effectively reproduces the RNA replication aspects of the HCV processes for molecules able to protect n4mBid cells from the life cycle but does not allow screens to identify inhibitors of entry HCV cytopathic effect. Many of the compounds in this library or infectious virus assembly and release. are approved for human therapeutic use in clinical trials or are The identification of a genotype 2a isolate of HCV that repro- structurally related to clinically approved molecules. Fig. S1 duces the entire viral life cycle in cell culture (5–7) promised to shows a set of representative cell viability results obtained from accelerate the discovery of antivirals targeting all aspects of HCV this screen. In total, >200 molecules mediated a statistically growth in a more true-to-life model system. Several recent reports significant increase in cell viability relative to untreated cells in describe systems that can in principle screen for inhibitors targeting response to HCV infection. Among the 56 hits that most strongly different steps of the HCV life cycle via the prevention of the protected n4mBid cells from the HCV cytopathic effect, we spread of cell culture-derived hepatitis C virus (HCVcc) infection fi – identi ed the known HCV inhibitors cyclosporin A (17), MK- in a cell monolayer (8 11). Very recently, one such screen based on 886 (12, 21), and TTNPB (22), as well as five additional com- a colorimetric readout following immunostaining with an anti-E2 fi pounds recently found in an anti-HCV drug screen targeting antibody identi ed inhibitors of multiple stages of the HCV life multiple aspects of the HCV life cycle (12). Numerous other cycle (12). Although effective, this approach is labor-intensive and molecules with reported anti-HCV activity appeared as weaker not readily amenable to high-throughput application, requiring antibodies and 12 washing steps in addition to a secondary screen to assess drug cytotoxicity. — — Author contributions: K.C. and Z.C. designed research; K.C. and R.L.S. performed research; We previously created a cell line n4mBid that sensitively C.M.R. contributed new reagents/analytic tools; K.C. and Z.C. analyzed data; C.M.R. pro- reports HCV infection via a cell death phenotype by introducing a vided conceptual advice; and K.C. and Z.C. wrote the paper. HCV NS3-4A protease-cleavable derivative of the proapoptotic The authors declare no conflict of interest. factor Bid, mBid (13), into the highly HCV-permissive hepatoma 1To whom correspondence should be addressed. E-mail: [email protected]. cell line Huh-7.5. In the present study, we demonstrate the utility This article contains supporting information online at www.pnas.org/cgi/content/full/ of the n4mBid cell line as a medium for the discovery of inhibitors 0915117107/DCSupplemental. 3764–3769 | PNAS | February 23, 2010 | vol. 107 | no. 8 www.pnas.org/cgi/doi/10.1073/pnas.0915117107 Downloaded by guest on September 28, 2021 Fig. 1. A n4mBid cell protection anti-HCV drug screen reports the presence of inhibitors targeting multiple stages of the HCV life cycle. (A) Schematic of screen. (B) Effect of known anti-HCV molecules on rescuing n4mBid cells from the HCV-induced cytopathic effect. (Upper) Drug dose–responses reporting n4mBid cell viability in the presence of HCV infection. (Lower) Drug cytotoxicity in the absence of HCV infection. (i and v) HCV replication inhibitors 2′CMA (•), VX-950 (▲), and cyclosporin A (■). (ii and vi) HCV entry-blocking anti-human CD81 mAb, JS-81. (iii and vii) The HCV assembly/release inhibitor naringenin. (iv and viii) IFNα-2a. Cell viability is presented as a percentage of mock-treated cells in the absence of both HCV infection and inhibitors. Values are the mean ± SD of two independent experiments carried out in duplicate. hits in our screen. A handful of known HCV inhibitors present molecules may interfere with mBid-mediated apoptosis, thus within the library did not protect n4mBid cells from HCV-mediated protecting cells from HCV-mediated cell death without specifi- cell death. This phenomenon is likely due to a combination of two cally influencing the HCV life cycle. Screening hits that enhance factors: (i) an extent of HCV life cycle inhibition insufficient to infectious HCV production (Table 1) may act, at least in part, alleviate the HCV cytopathic effect and (ii) drug cytotoxicity. For through alleviation of a cytopathic effect downstream of HCV example, the estrogen receptor antagonist tamoxifen, a HCV rep- infection rather than directly targeting the HCV life cycle, thus lication inhibitor present in the library, did not appear as a hit, likely increasing HCV productivity by making the producer cells less due to its significant cytotoxicity even while inhibiting HCV repli- susceptible to HCV-induced stress. cation at 1 μM(23). We commenced characterization of the leading 55 drug hits from Effect of Selected Inhibitors on Viral Entry. Several of the HCV our screen (excluding cyclosporin A) by measuring their dose- inhibitor hits from our screen strongly inhibited entry of HCVpp dependent effects on the protection of n4mBid cells from the HCV into Huh-7.5 cells (Table 1 and Fig. S3). Six of these compounds cytopathic effect, as well as on HCV-independent cellular cytotox- exhibited a strong dose-dependent inhibition of HCVpp entry icity, confirming that all of the leading 55 drug hits mediated a dose- without significant cytotoxicity (Fig. 2). Five of these six compounds dependent protection phenotype from HCV-triggered cell death inhibited HCVpp entry without significantly affecting entry of VSV- (Fig.
Load more

Recommended publications
  • The Uptake and Release of Serotonin and Dopamine Associated with Locust (Locusta Migratoria) Salivary Glands
    The Journal of Experimental Biology 199, 699–709 (1996) 699 Printed in Great Britain © The Company of Biologists Limited 1996 JEB0166 THE UPTAKE AND RELEASE OF SEROTONIN AND DOPAMINE ASSOCIATED WITH LOCUST (LOCUSTA MIGRATORIA) SALIVARY GLANDS DECLAN W. ALI AND IAN ORCHARD Department of Zoology, 25 Harbord Street, University of Toronto, Toronto, Ontario, Canada M5S 1A1 Accepted 24 October 1995 Summary The uptake and release characteristics of dopamine and affinity components. [3H]dopamine uptake is Na+- serotonin in the salivary glands of the locust Locusta independent and can be partially reduced by a challenge migratoria were examined. Cyclic AMP levels were with high-K+ saline and by a challenge with ice-cold saline. determined in salivary glands in which the salivary nerve Uptake inhibitors are capable of blocking the uptake of was stimulated under different experimental paradigms. radiolabelled serotonin and dopamine. There is a Ca2+- Stimulation of the salivary nerve leads to time- and dependent efflux of [3H]serotonin and [3H]dopamine from frequency-dependent elevations of cyclic AMP levels in the previously loaded salivary glands in response to glands. The potent and specific D1 receptor antagonist stimulation of the salivary nerve and to treatment with a SCH-23390 is capable of partially inhibiting the high-K+ saline. electrophysiologically induced elevations of cyclic AMP levels. The salivary glands appear to possess uptake transporters for serotonin and dopamine. [3H]serotonin Key words: salivary glands, insect, dopamine, serotonin, cyclic AMP, uptake is Na+-dependent and is composed of high- and low- uptake, release, locust, Locusta migratoria. Introduction Locust salivary glands are innervated via the salivary nerve, evidence to suggest that dopamine and serotonin alter salivary nerve 7b, which is a branch of nerve 7 that originates from the secretory rates (Baines et al.
    [Show full text]
  • Synthesis of Novel 6-Nitroquipazine Analogs for Imaging the Serotonin Transporter by Positron Emission Tomography
    University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Professional Papers Graduate School 2006 Synthesis of novel 6-nitroquipazine analogs for imaging the serotonin transporter by positron emission tomography David B. Bolstad The University of Montana Follow this and additional works at: https://scholarworks.umt.edu/etd Let us know how access to this document benefits ou.y Recommended Citation Bolstad, David B., "Synthesis of novel 6-nitroquipazine analogs for imaging the serotonin transporter by positron emission tomography" (2006). Graduate Student Theses, Dissertations, & Professional Papers. 9590. https://scholarworks.umt.edu/etd/9590 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. Maureen and Mike MANSFIELD LIBRARY The University of Montana Permission is granted by the author to reproduce this material in its entirety, provided that this material is used for scholarly purposes and is properly cited in published works and reports. **Please check "Yes" or "No" and provide signature** Yes, I grant permission No, I do not grant permission Author's Signature: Date: C n { ( j o j 0 ^ Any copying for commercial purposes or financial gain may be undertaken only with the author's explicit consent. 8/98 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
    [Show full text]
  • Skim - a Generalized Literature-Based Discovery System For
    bioRxiv preprint doi: https://doi.org/10.1101/2020.10.16.343012; this version posted October 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SKiM - A generalized literature-based discovery system for uncovering novel biomedical knowledge from PubMed Kalpana Raja1, John Steill1, Ian Ross2, Lam C Tsoi3,4,5, Finn Kuusisto1, Zijian Ni6, Miron Livny2, James Thomson1,7 and Ron Stewart1* 1Regenerative Biology, Morgridge Institute for Research, Madison, WI, USA 2Center for High Throughput Computing, Computer Sciences Department, University of Wisconsin, Madison, WI, USA 3Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA 4Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA 5Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA 6Department of Statistics, University of Wisconsin, Madison, WI, USA 7Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI, USA *Corresponding author Email: [email protected] Phone: (608) 316-4349 Home page: https://morgridge.org/profile/ron-stewart/ bioRxiv preprint doi: https://doi.org/10.1101/2020.10.16.343012; this version posted October 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Literature-based discovery (LBD) uncovers undiscovered public knowledge by linking terms A to C via a B intermediate. Existing LBD systems are limited to process certain A, B, and C terms, and many are not maintained. We present SKiM (Serial KinderMiner), a generalized LBD system for processing any combination of A, Bs, and Cs.
    [Show full text]
  • Antidepressant Potential of Nitrogen-Containing Heterocyclic Moieties: an Updated Review
    Review Article Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review Nadeem Siddiqui, Andalip, Sandhya Bawa, Ruhi Ali, Obaid Afzal, M. Jawaid Akhtar, Bishmillah Azad, Rajiv Kumar Department of ABSTRACT Pharmaceutical Chemistry, Depression is currently the fourth leading cause of disease or disability worldwide. Antidepressant is Faculty of Pharmacy, Jamia Hamdard approved for the treatment of major depression (including paediatric depression), obsessive-compulsive University, Hamdard disorder (in both adult and paediatric populations), bulimia nervosa, panic disorder and premenstrual Nagar, New Delhi - dysphoric disorder. Antidepressant is a psychiatric medication used to alleviate mood disorders, such as 110 062, India major depression and dysthymia and anxiety disorders such as social anxiety disorder. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a Address for correspondence: risk, despite claims of superior efficacy. Our current understanding of its pathogenesis is limited and existing Dr. Sandhya Bawa, E-mail: sandhyabawa761@ treatments are inadequate, providing relief to only a subset of people suffering from depression. Reviews of yahoo.com literature suggest that heterocyclic moieties and their derivatives has proven success in treating depression. Received : 08-02-11 Review completed : 15-02-11 Accepted : 17-02-11 KEY WORDS: Antidepressant, depression, heterocyclic epression is a chronic, recurring and potentially life- monoamine oxidase inhibitors (MAOIs, e.g. Nardil®) tricyclic D threatening illness that affects up to 20% of the population antidepressants (TCAs, e.g. Elavil). They increases the synaptic across the globe.[1] The etiology of the disease is suboptimal concentration of either two (5-HT and NE) or all three (5-HT, concentrations of the monoamine neurotransmitters serotonin NE and dopamine (DA)) neurotransmitters.
    [Show full text]
  • Serotonergic Activiation of Locomotor Behavior and Posture in One-Day
    Behavioural Brain Research 302 (2016) 104–114 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report Serotonergic activation of locomotor behavior and posture in one-day old rats ∗ Hillary E. Swann, R. Blaine Kempe, Ashley M. Van Orden, Michele R. Brumley Idaho State University, Department of Psychology, Pocatello, ID, United States h i g h l i g h t s • Quipazine induced air-stepping, locomotion, and posture in P1 rats. • During air-stepping, steps maintained highly anti-phase coordination. • Forms of locomotion included pivoting, crawling, and some walking. • Advanced posture such as head elevation and locomotor stances were shown. a r t i c l e i n f o a b s t r a c t Article history: The purpose of this study was to determine what dose of quipazine, a serotonergic agonist, facilitates Received 11 July 2015 air-stepping and induces postural control and patterns of locomotion in newborn rats. Subjects in both Received in revised form experiments were 1-day-old rat pups. In Experiment 1, pups were restrained and tested for air-stepping 18 November 2015 in a 35-min test session. Immediately following a 5-min baseline, pups were treated with quipazine (1.0, Accepted 5 January 2016 3.0, or 10.0 mg/kg) or saline (vehicle control), administered intraperitoneally in a 50 ␮L injection. Bilateral Available online 12 January 2016 alternating stepping occurred most frequently following treatment with 10.0 mg/kg quipazine, however the percentage of alternating steps, interlimb phase, and step period were very similar between the 3.0 Keywords: and 10.0 mg/kg doses.
    [Show full text]
  • Enhancement of Specific [3Hlquipazine Binding with Triton X-100-Treated Membranes from Rat Cortex
    Improvement of 5-HT3 Receptor Binding Assay: Enhancement of Specific [3HlQuipazine Binding with Triton X-100-Treated Membranes from Rat Cortex Teruaki Une, Kiyoshi Furukawa and Masanobu Komiya Department of Pharmacology, Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94, Enokicho, Suita, Osaka 564, Japan Received April 9, 1991 Accepted July 1, 1991 ABSTRACT-The 5-hydroxytryptamine (5-HT)3 receptor binding assay using [3H]quipazine was examined. It was impossible to obtain specific [3H]quipazine bind ing with the membrane fractions from rat cortex prepared by the usual procedure. When the membranes were pretreated with detergent Triton X-100, the ratio of spe cific [3H]quipazine binding markedly increased, depending upon the concentration of Triton X-100 in the range of 0.01-0.1% (w/v). At a concentration of more than 0.05%, the specific binding reached a maximum of 55 to 60% of the total binding. The specific [3H]quipazine binding to the Triton X-100-treated membranes was re versible and was potently inhibited by several 5-HT3 antagonists, while 5-HT], 5-HT2 receptor antagonists and other receptor-specific ligands had no effect on the binding. Scatchard analysis indicated a single class of binding sites with a Kd of 0.62 nM and Bmax of 97 fmol/mg protein. Thus, the Triton X-100-treated membranes retained the characteristics of 5-HT3 binding sites, making it possible to use [3H]quipazine for a 5 HT3 receptor binding assay with a high ratio of specific binding. Serotonin (5-HT) receptors have been di their method, because of high percentages of vided into three different subtypes: 5-HT1, 5 non-specific binding.
    [Show full text]
  • A Validated Animal Model for the Serotonin Syndrome
    A validated animal model for the Serotonin Syndrome Inaugural–Dissertation to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) submitted to the Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin by Robert Haberzettl from Berlin, Germany 2014 This thesis is based on research conducted from 2008 to 2014 at the Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universität Berlin, in Berlin, Germany, under the supervision of Prof. Dr. med. Heidrun Fink and Dr. vet. med. Bettina Bert. Reviewer 1. Reviewer: Prof. Dr. med. Heidrun Fink Institute of Pharmacology and Toxicology Department of Veterinary Medicine Freie Universität Berlin 2. Reviewer: Prof. Constance Scharff, PhD Institute of Biology Department of Biology, Chemistry and Pharmacy Freie Universität Berlin Date of defence: 24.06.2015 ii Declaration I hereby declare that the work presented in this thesis has been conducted independently and without any inappropriate support, and that all sources of content, experimental or intellectual, are suitably referenced and acknowledged. I further declare that this thesis has not been submitted before, either in the same or a different form, to this or any other university for a degree. Robert Haberzettl Berlin, den 01.09.2014 iii Acknowledgement My sincere gratitude goes to Professor Dr. Heidrun Fink, who gave me the opportunity to work in her institute and guided me throughout the entire doctoral period. I have learned much in the field of science but also a lot about life. To Dr. Bettina Bert, I am grateful for her guidance and support. Dr. Jan Brosda, Dr. Nicole Marquardt and Alexandra Wiczorek, I am grateful for your help, advice and friendship.
    [Show full text]
  • 5-HT Receptors Review
    Neuronal 5-HT Receptors and SERT Nicholas M. Barnes1 and John F. Neumaier2 1Cellular and Molecular Neuropharmacology Research Group, Section of Neuropharmacology and Neurobiology, Clinical and Experimental Medicine, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT UK and 2Department of Psychiatry, University of Washington, Seattle, WA 98104 USA. Correspondence: [email protected] and [email protected] Nicholas Barnes is Professor of Neuropharmacology at the University of Birmingham Medical School, and focuses on serotonin receptors and the serotonin transporter. John Neumaier is Professor of Psychiatry and Behavioural Sciences and Director of the Division of Neurosciences at the University of Washington. His research concerns the role of serotonin receptors in emotional behavior. Contents Introduction Introduction ........................................................................ 1 5-hydroxytryptamine (5-HT, serotonin) is an ancient biochemical manipulated through evolution to be DRIVING RESEARCH FURTHER The 5-HT1 Receptor Family ............................................... 1 utilized extensively throughout the animal and plant kingdoms. Mammals employ 5-HT as a 5-HT Receptors ............................................................ 2 1A neurotransmitter within the central and peripheral nervous systems, and also as a local hormone in 5-HT Receptors ............................................................ 2 1B numerous other tissues, including the gastrointestinal tract, the cardiovascular
    [Show full text]
  • Sexual Dysfunction, Depression and Antidepressants: a Translational Approach
    Chapter 4 Sexual Dysfunction, Depression and Antidepressants: A Translational Approach Jocelien D.A. Olivier, Diana C. Esquivel Franco, Marcel D. Waldinger and Berend Olivier Additional information is available at the end of the chapter http://dx.doi.org/10.5772/intechopen.69105 Abstract Major depression is frequently associated with sexual dysfunctions. Most antidepres- sants, especially selective serotonin reuptake inhibitors (SSRIs), induce additional sexual side effects and, although effective antidepressants, deteriorate sexual symptoms, which are the main reason that patients stop antidepressant treatment. Many strategies have been used to circumvent the additional sexual side effects, but results are rather disap- pointing. Recently, new antidepressants have been introduced, vilazodone and vortiox- etine, which seem to lack sexual side effects in the early registration trials. Much research with large numbers of depressed patients and adequate methodological tools still has to confirm in daily use the absence of sexual side effects of new antidepressants. Animal models that in an early phase of drug development may predict putative sexual side effects of new antidepressants are extremely useful and could speed up development of new antidepressants. A rat model of sexual behavior is described that has a very high predictive validity for sexual side effects in man. Several characteristics of present antide- pressants with regard to sexual dysfunctions are also present in the rat model and estab- lish its validity. The animal model can also be used in the search for new psychotropics without sexual side effects or for drugs with sexual stimulating activity. Keywords: depression, sexual dysfunction, antidepressants, sexual side effects, SSRI, animal model 1.
    [Show full text]
  • Multi-Discipline Review
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209500Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 209500 Priority or Standard Standard Submit Date(s) September 27, 2018 Received Date(s) September 27, 2018 PDUFA Goal Date December 27, 2019 Division/Office Division of Psychiatry / Office of Drug Evaluation-I Review Completion Date December 20, 2019 Established/Proper Name Lumateperone (Proposed) Trade Name Caplyta Pharmacologic Class Atypical Antipsychotic Code name ITI-007 Applicant Intra-Cellular Therapies, Inc. Dosage form 42 mg Capsules Applicant proposed Dosing 42 mg by mouth once daily Regimen Applicant Proposed Schizophrenia/Adults Indication(s)/Population(s) Applicant Proposed 58214004 | Schizophrenia (disorder) SNOMED CT Indication Disease Term for each Proposed Indication Recommendation on Approval Regulatory Action Recommended Schizophrenia/Adults Indication(s)/Population(s) (if applicable) Recommended SNOMED 58214004 | Schizophrenia (disorder) CT Indication Disease Term for each Indication (if applicable) Recommended Dosing 42 mg by mouth once daily Regimen 1 Version date: October 12, 2018 Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone) Table of Contents Table of
    [Show full text]
  • Serotonin Receptors and Drugs Affecting Serotonergic Neurotransmission R ICHARD A
    Chapter 11 Serotonin Receptors and Drugs Affecting Serotonergic Neurotransmission R ICHARD A. GLENNON AND MAŁGORZATA DUKAT Drugs Covered in This Chapter* Antiemetic drugs (5-HT3 receptor • Rizatriptan • Imipramine antagonists) • Sumatriptan • Olanzapine • Alosetron • Zolmitriptan • Propranolol • Dolasetron Drug for the treatment of • Quetiapine • Granisetron irritable bowel syndrome (5-HT4 • Risperidone • Ondansetron agonists) • Tranylcypromine • Palonosetron • Tegaserod • Trazodone • Tropisetron Drugs for the treatment of • Ziprasidone Drugs for the treatment of neuropsychiatric disorders • Zotepine migraine (5-HT1D/1F receptor agonists) • Buspirone Hallucinogenic agents • Almotriptan • Citalopram • Lysergic acid diethylamide • Eletriptan • Clozapine • 2,5-dimethyl-4-bromoamphetamine • Frovatriptan • Desipramine • 2,5-dimethoxy-4-iodoamphetamine • Naratriptan • Fluoxetine Abbreviations cAMP, cyclic adenosine IBS-C, irritable bowel syndrome with nM, nanomoles/L monophosphate constipation MT, melatonin CNS, central nervous system IBS-D, irritable bowel syndrome with MTR, melatonin receptor 5-CT, 5-carboxamidotryptamine diarrhea NET, norepinephrine reuptake transporter DOB, 2,5-dimethyl-4-bromoamphetamine LCAP, long-chain arylpiperazine 8-OH DPAT, 8-hydroxy-2-(di-n- DOI, 2,5-dimethoxy-4-iodoamphetamine L-DOPA, L-dihydroxyphenylalanine propylamino)tetralin EMDT, 2-ethyl-5-methoxy-N,N- LSD, lysergic acid diethylamide PMDT, 2-phenyl-5-methoxy-N,N- dimethyltryptamine MAO, monomaine oxidase dimethyltryptamine GABA, g-aminobutyric acid MAOI,
    [Show full text]
  • Neuronal 5-HT Receptors and SERT
    NeuronalTocris 5-HT Scientific Receptors Review and SERTSeries Tocri-lu-2945 Neuronal 5-HT Receptors and SERT Nicholas M. Barnes1 and Introduction 2 John F. Neumaier 5-hydroxytryptamine (5-HT, serotonin) is an ancient biochemical 1Cellular and Molecular Neuropharmacology Research Group, manipulated through evolution to be utilized extensively Section of Neuropharmacology and Neurobiology, Clinical and throughout the animal and plant kingdoms. Mammals employ Experimental Medicine, The Medical School, University of 5-HT as a neurotransmitter within the central and peripheral Birmingham, Edgbaston, Birmingham B15 2TT, UK and nervous systems, and also as a local hormone in numerous other tissues, including the gastrointestinal tract, the cardiovascular 2Department of Psychiatry, University of Washington, Seattle, WA system and immune cells. This multiplicity of function implicates 98104, USA. Correspondence: [email protected] and 5-HT in a vast array of physiological and pathological processes. [email protected] This plethora of roles has consequently encouraged the Nicholas Barnes is Professor of Neuropharmacology at the development of many compounds of therapeutic value, including University of Birmingham Medical School, and focuses on various antidepressant, antipsychotic and antiemetic drugs. serotonin receptors and the serotonin transporter. John Neumaier Part of the ability of 5-HT to mediate a wide range of actions arises is Professor of Psychiatry and Behavioural Sciences and Director from the imposing number of 5-HT receptors.1 of the Division of Neurosciences at the University of Washington. Numerous 5-HT His research concerns the role of serotonin receptors in emotional receptor families and subtypes have evolved. Currently, 18 genes behavior. are recognized as being responsible for 14 distinct mammalian 5-HT receptor subtypes, which are divided into 7 families, all but one of which are members of the G-protein coupled receptor (GPCR) superfamily.
    [Show full text]