K+ Channel Modulators Product ID Product Name Description D3209 Diclofenac Sodium Salt NSAID; COX-1/2 Inhibitor, Potential K+ Channel Modulator
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Mrna Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases Upon Antidepressant Treatment
International Journal of Molecular Sciences Article mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment Cosima Rhein 1,2,* , Iulia Zoicas 1 , Lena M. Marx 1, Stefanie Zeitler 1, Tobias Hepp 2,3, Claudia von Zimmermann 1, Christiane Mühle 1 , Tanja Richter-Schmidinger 1, Bernd Lenz 1,4 , Yesim Erim 2, Martin Reichel 1,† , Erich Gulbins 5 and Johannes Kornhuber 1 1 Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; [email protected] (I.Z.); [email protected] (L.M.M.); [email protected] (S.Z.); [email protected] (C.v.Z.); [email protected] (C.M.); [email protected] (T.R.-S.); [email protected] (B.L.); [email protected] (M.R.); [email protected] (J.K.) 2 Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany; [email protected] (T.H.); [email protected] (Y.E.) 3 Institute of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany 4 Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, D-68159 Mannheim, Germany 5 Department of Molecular Biology, University Hospital, University of Duisburg-Essen, D-45147 Essen, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-9131-85-44542 Citation: Rhein, C.; Zoicas, I.; Marx, † Current address: Department of Nephrology and Medical Intensive Care, Charité—Universitätsmedizin L.M.; Zeitler, S.; Hepp, T.; von Berlin, Berlin, Germany. -
Therapeutic Potential of RQ-00311651, a Novel T-Type Ca
Research Paper Therapeutic potential of RQ-00311651, a novel T-type Ca21 channel blocker, in distinct rodent models for neuropathic and visceral pain Fumiko Sekiguchia, Yuma Kawaraa, Maho Tsubotaa, Eri Kawakamia, Tomoka Ozakia, Yudai Kawaishia, Shiori Tomitaa, Daiki Kanaokaa, Shigeru Yoshidab, Tsuyako Ohkuboc, Atsufumi Kawabataa,* Abstract 21 T-type Ca channels (T channels), particularly Cav3.2 among the 3 isoforms, play a role in neuropathic and visceral pain. We thus characterized the effects of RQ-00311651 (RQ), a novel T-channel blocker, in HEK293 cells transfected with human Cav3.1 or 21 Cav3.2 by electrophysiological and fluorescent Ca signaling assays, and also evaluated the antiallodynic/antihyperalgesic activity of RQ in somatic, visceral, and neuropathic pain models in rodents. RQ-00311651 strongly suppressed T currents when tested at holding potentials of 265 ; 260 mV, but not 280 mV, in the Cav3.1- or Cav3.2-expressing cells. RQ-00311651 also inhibited high K1-induced Ca21 signaling in those cells. In mice, RQ, administered intraperitoneally (i.p.) at 5 to 20 mg/kg or orally at 20 to 40 mg/kg, significantly suppressed the somatic hyperalgesia and visceral pain-like nociceptive behavior/referred hyperalgesia caused by intraplantar and intracolonic administration of NaHS or Na2S, H2S donors, respectively, which involve the enhanced activity of Cav3.2 channels. RQ-00311651, given i.p. at 5 to 20 mg/kg, exhibited antiallodynic or antihyperalgesic activity in rats with spinal nerve injury–induced neuropathy or in rats and mice with paclitaxel-induced neuropathy. Oral and i.p. RQ at 10 to 20 mg/kg also suppressed the visceral nociceptive behavior and/or referred hyperalgesia accompanying cerulein-induced acute pancreatitis and cyclophosphamide-induced cystitis in mice. -
Z944: an Oral T-Type Calcium Channel Modulator for the Treatment of Pain Margaret S
Z944: An oral T-type calcium channel modulator for the treatment of pain Margaret S. Lee, PhD Ion Channel Retreat 2014, June 25, 2014 T-type Calcium Channels: A Novel Target for Pain and Other CNS Disorders • T-type calcium channels are voltage gated and comprised of three subtypes: Cav3.1, Cav3.2 & Cav3.3 • Expressed in Central and Peripheral Nervous System, including primary afferent, dorsal horn neurons, thalamus and somatosensory cortex • Contribute to neuronal excitability, synaptic excitation, burst firing and action potential trains, and also lower threshold for action potentials Pain Signaling Thalamocortical Connectivity Source: Adapted from Zamponi, et al., Brain Res. Reviews. 2009 Source: Adapted from Park, et al., Frontiers Neural Circuits. 2013 • Rodent neuropathic and IBS pain models exhibit increased • Thalamocortical dysrythmia linked to CNS indications, e.g. T-type current density motor, neuropsychiatric and chronic pain syndromes • Gene knockout or antisense reduces pain in neuropathic, • Mutations in T-type channels are found in rodent and acute and visceral pain models human excitability disorders • T-type channel blockers attenuate neuropathic, • Approved anti-convulsants (e.g. ethosuximide, valproate) inflammatory, acute and visceral pain in animal models target T-type channels © Copyright Neuromed 2 Z944 is a Potent, Selective Blocker of T-type Calcium Channels IC50 (nM) Channel 30% Fold-Selectivity Closed Inactivated (30% Inactivated) CaV3.1(human, exogenous) 50 130 1 CaV3.2 (human, exogenous) 160 540 3.2 CaV3.3 (human, exogenous) 110 260 2.2 N-type (rat, exogenous) 11,000 150,000 220 L-type cardiac calcium (rat CaV1.2) 32,000 -- 640 Cardiac Sodium (human NaV1.5) 100,000 -- 2000 hERG channel (human) 7,800 -- 156 • Displays enhanced potency for the inactivated state across T-type channels • Z944 block of Cav3.2 is more pronounced during high-frequency firing • Z944 has >150-fold selectivity vs. -
GABA Receptors
D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43. -
Rediscovery of Fexinidazole
New Drugs against Trypanosomatid Parasites: Rediscovery of Fexinidazole INAUGURALDISSERTATION zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Marcel Kaiser aus Obermumpf, Aargau Basel, 2014 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Dieses Werk ist unter dem Vertrag „Creative Commons Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 3.0 Schweiz“ (CC BY-NC-ND 3.0 CH) lizenziert. Die vollständige Lizenz kann unter creativecommons.org/licenses/by-nc-nd/3.0/ch/ eingesehen werden. 1 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel auf Antrag von Prof. Reto Brun, Prof. Simon Croft Basel, den 10. Dezember 2013 Prof. Dr. Jörg Schibler, Dekan 2 3 Table of Contents Acknowledgement .............................................................................................. 5 Summary ............................................................................................................ 6 Zusammenfassung .............................................................................................. 8 CHAPTER 1: General introduction ................................................................. 10 CHAPTER 2: Fexinidazole - A New Oral Nitroimidazole Drug Candidate Entering Clinical Development for the Treatment of Sleeping Sickness ........ 26 CHAPTER 3: Anti-trypanosomal activity of Fexinidazole – A New Oral Nitroimidazole Drug Candidate for the Treatment -
Ceramide and Related Molecules in Viral Infections
International Journal of Molecular Sciences Review Ceramide and Related Molecules in Viral Infections Nadine Beckmann * and Katrin Anne Becker Department of Molecular Biology, University of Duisburg-Essen, 45141 Essen, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-201-723-1981 Abstract: Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit. Keywords: ceramide; acid sphingomyelinase; sphingolipids; lipid-rafts; α-galactosylceramide; viral Citation: Beckmann, N.; Becker, K.A. -
No Involvement of Acid Sphingomyelinase in the Secretion of IL-6 From
1 No Involvement of Acid Sphingomyelinase in the Secretion of IL-6 from Alveolar Macrophages in Rat Tomoo Ito, Chikako Oyama, Hirokazu Arai, Tsutomu Takahashi Department of Pediatrics, Akita University Graduate School of Medicine, Akita-shi, Akita, 010-8543, Japan Correspondence: Tsutomu Takahashi, M.D. Department of Pediatrics, Akita University Graduate School of Medicine, 1-1-1 hondo, Akita 010-8543, Japan Tel: 018-884-6159 FAX: 018-836-2620 E-mail: [email protected] 1 2 Key words: chronic lung disease of the newborn, alveolar macrophage, acid sphingomyelinase, Running title: Acid Sphingomyelinase in CLD of the Newborn 2 3 Abstract Chronic lung disease (CLD) of the newborn is a major problem in neonatology. Activation of alveolar macrophages has been implicated in the pathogenesis of CLD. Acid sphingomyelinase (ASM) responds to diverse cellular stressors, including lipopolysaccharide (LPS) stimulation. Recently, functional inhibitors of acid sphingomyelinase (FIASMAs) have been described as a large group of compounds that inhibit ASM. Here, we used maternal intra-peritoneal LPS injection to model CLD in the infant rat lung. Using this model, we studied ASM activity in the infant rat lung and the effects of FIASMAs on release of interleukin-6 (IL-6) from LPS-stimulated alveolar macrophages. Maternal exposure to LPS non-significantly increased ASM activities in the infant rat lung. FIASMAs significantly decreased ASM activity of LPS-stimulated alveolar macrophages. In addition, some FIASMAs suppressed the release of IL-6 from LPS-stimulated alveolar macrophages during the early response phase. However, FIASMAs did not suppress the release of IL-6 from LPS-stimulated alveolar macrophages. -
Membrane Stabilizer Medications in the Treatment of Chronic Neuropathic Pain: a Comprehensive Review
Current Pain and Headache Reports (2019) 23: 37 https://doi.org/10.1007/s11916-019-0774-0 OTHER PAIN (A KAYE AND N VADIVELU, SECTION EDITORS) Membrane Stabilizer Medications in the Treatment of Chronic Neuropathic Pain: a Comprehensive Review Omar Viswanath1,2,3 & Ivan Urits4 & Mark R. Jones4 & Jacqueline M. Peck5 & Justin Kochanski6 & Morgan Hasegawa6 & Best Anyama7 & Alan D. Kaye7 Published online: 1 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review Neuropathic pain is often debilitating, severely limiting the daily lives of patients who are affected. Typically, neuropathic pain is difficult to manage and, as a result, leads to progression into a chronic condition that is, in many instances, refractory to medical management. Recent Findings Gabapentinoids, belonging to the calcium channel blocking class of drugs, have shown good efficacy in the management of chronic pain and are thus commonly utilized as first-line therapy. Various sodium channel blocking drugs, belonging to the categories of anticonvulsants and local anesthetics, have demonstrated varying degrees of efficacy in the in the treatment of neurogenic pain. Summary Though there is limited medical literature as to efficacy of any one drug, individualized multimodal therapy can provide significant analgesia to patients with chronic neuropathic pain. Keywords Neuropathic pain . Chronic pain . Ion Channel blockers . Anticonvulsants . Membrane stabilizers Introduction Neuropathic pain, which is a result of nervous system injury or lives of patients who are affected. Frequently, it is difficult to dysfunction, is often debilitating, severely limiting the daily manage and as a result leads to the progression of a chronic condition that is, in many instances, refractory to medical This article is part of the Topical Collection on Other Pain management. -
Drugs, Herg and Sudden Death A.M
Cell Calcium 35 (2004) 543–547 Drugs, hERG and sudden death A.M. Brown a,b,∗ a MetroHealth Campus, Case Western Reserve University, Cleveland, OH 44128, USA b ChanTest, Inc., 14656 Neo Parkway, Cleveland, OH 44128, USA Received 1 December 2003; accepted 12 January 2004 Abstract Early recognition of potential QT/TdP liability is now an essential component of the drug discovery/drug development program. The hERG assay is an indispensable step and a high-quality assay must accompany any investigational new drug (IND) application. While it is the gold standard at present, the hERG assay is too labor-intensive and too low throughput to be used as a screen early in the discovery/development process. A variety of indirect high throughput screens have been used. © 2004 Elsevier Ltd. All rights reserved. Keywords: Screens; Throughput; hERG; QT; Sudden death Sudden cardiac death due to non-cardiac drugs is the ma- fexofenadine, the active metabolite for which terfenadine is jor safety issue presently facing the pharmaceutical industry a pro-drug, became available. and the agencies that regulate it. In recent years, several TdP is linked to defective repolarization and prolongation blockbuster drugs such as terfenadine (Seldane), cisapride of the QT interval of the EKG; at the cellular level the (Propulsid), grepafloxacin (Raxar) and terodiline have been duration of the cardiac action potential (APD) is prolonged. withdrawn from major markets, other drugs such as sertin- The major membrane currents that might be involved are dole (Serlect) have been withdrawn prior to marketing and shown in Fig. 1. still others such as ziprasidone (Zeldox) have undergone In 1993, Woosley’s lab showed that terfenadine blocked + severe labeling restrictions. -
Atomistic Insights of Calmodulin Gating of Complete Ion Channels
International Journal of Molecular Sciences Review Atomistic Insights of Calmodulin Gating of Complete Ion Channels Eider Núñez y, Arantza Muguruza-Montero y and Alvaro Villarroel * Biofisika Institute (CSIC, UPV/EHU), University of the Basque Country, 48940 Leioa, Spain; [email protected] (E.N.); [email protected] (A.M.-M.) * Correspondence: [email protected]; Tel.: +34-9460-13225 These authors contribute equally to this work. y Received: 18 December 2019; Accepted: 12 February 2020; Published: 14 February 2020 Abstract: Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca2+ signaling from the extracellular medium depends both on membrane potential, especially controlled by ion channels selective to K+, and direct permeation of this cation through specialized channels. Calmodulin (CaM), through direct binding to these proteins, participates in setting the membrane potential and the overall permeability to Ca2+. Over the past years many structures of complete channels in complex with CaM at near atomic resolution have been resolved. In combination with mutagenesis-function, structural information of individual domains and functional studies, different mechanisms employed by CaM to control channel gating are starting to be understood at atomic detail. Here, new insights regarding four types of tetrameric channels with six transmembrane (6TM) architecture, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1–5, and its regulation by CaM are described structurally. Different CaM regions, N-lobe, C-lobe and EF3/EF4-linker play prominent signaling roles in different complexes, emerging the realization of crucial non-canonical interactions between CaM and its target that are only evidenced in the full-channel structure. -
2019 Instrumentation and Consumable Catalog 2 INSTRUMENTATION and CONSUMABLE CATALOG
PRODUCT CATALOG 2019 Instrumentation and Consumable Catalog 2 INSTRUMENTATION AND CONSUMABLE CATALOG Resolvex® A200 Part Numbers: A200 96: 253-1160 Resolvex® A200 96 Resolvex A200 Standalone work station for automated sample preparation. The compact benchtop offers the one stop solution for automating sample preparation utilizing creation of multiple work flows, and programmable dispensing of up to 11 solvents. Along with its innovative positive pressure system leading to clean samples, improving accuracy, throughput and enhancing the Life time of your analytical instrument. The A200 comes with an easy to use touch screen interface allowing for easy set up of multiple work flows. In addition the light curtain safety feature will release gas pressure when manifold is activated to prevent any injuries. INSTRUMENTATION AND CONSUMABLE CATALOG 3 Resolvex® A100 Part Numbers: A100 96: 253-0019 A100 48: 253-0014 Resolvex® A100 Standalone work station for automated sample preparation. The compact benchtop offers the one stop solution for automating sample preparation utilizing creation of multiple work flows, and programmable dispensing of up to 11 solvents. Along with its innovative positive pressure system leading to clean samples, improving accuracy, throughput and enhancing the Life time of your analytical instrument. The A100 comes in 96 and 4 configuration allowing for for automated Work Flow solutions in multiple SPE formats. 4 INSTRUMENTATION AND CONSUMABLE CATALOG Resolvex® M10 96/M10 96 XT/M10 48 Part Numbers: M10 96 XT: 288-0006 M10 96: 288-0001 M10 48: 289-0004 Resolvex® M10 Standalone work station for Positive Pressure solid phase extraction. The manual Resolvex M10 48 and 96 are positive pressure manifold for 1, 3, and 6 ml cartridges, or 1ml 96 well plates. -
Study Protocol 64565111EDI1002
NCT03586830 Janssen Research & Development * Clinical Protocol Protocol Title A Randomized, Double-blind Placebo-controlled, Parallel-group, Multicenter, Dose- ranging Study to Evaluate the Safety and Efficacy of JNJ-64565111 in Severely Obese Subjects with Type 2 Diabetes Mellitus Short Title Evaluation of JNJ-64565111 in Severely Obese Subjects with Type 2 Diabetes Mellitus Protocol 64565111OBE2002; Phase 2b AMENDMENT 1 JNJ-64565111 *Janssen Research & Development is a global organization that operates through different legal entities in various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact Information page that accompanies the protocol. US sites of this study will be conducted under US Food & Drug Administration IND regulations (21 CFR Part 312).] Status: Approved Date: 23 August 2018 Prepared by: Janssen Research & Development, LLC EDMS number: EDMS-ERI-156156741, 2.0 GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory requirements. Confidentiality Statement The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them.