DOCSLIB.ORG

Drug Metabolism and Pharmacokinetics in the Lead Optimisation of Novel Positive Allosteric Modulators of Α1 Strychnine Sensitive Glycine Receptors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Drug Metabolism and Pharmacokinetics in the Lead Optimisation of Novel Positive Allosteric Modulators of Α1 Strychnine Sensitive Glycine Receptors Drug Metabolism and Pharmacokinetics in the Lead Optimisation of Novel Positive Allosteric Modulators of α1 Strychnine Sensitive Glycine Receptors Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor of Philosophy by Elinor Wylde October 2015 Declaration This thesis is the result of my own work. The material contained in the thesis has not been presented, nor is currently being presented, either wholly or in part for any other degree or other qualification. Elinor Wylde This research was carried out in the Liverpool School of Tropical Medicine and in the Department of Pharmacology at the University of Liverpool Acknowledgments I would like to thank my supervisors Prof. Martin Leuwer and Prof. Paul O’Neill for the opportunity to take part in this research and for all the help and guidance they have given over the course of my PhD. I would like to thank the members of the research group and our collaborators. A special thanks to Dr Chandra Pidathala and Dr Lee Taylor of the Liverpool University, Chemistry Department for sharing their research with me. Thank you to the staff and students at the Liverpool School of Tropical Medicine and in the Department of Pharmacology, who helped me set up my research and provided me with an excellent working environment. Particularly to Dr Ally Shone, who kindly offered to take me under her wing and to whom I am extremely grateful. Big thanks to my family, especially my parents, Kate and John for supporting me over throughout my undergraduate and postgraduate study. Thank you to my Aunt, Lynda who has offered me a place to stay during my studies. Finally, I would like to express gratitude all my friends who have provided me with a great deal of emotional support. To my best friend Laura, who has always been with me from primary school to postgraduate study. Lastly to Emma, Sammy, Tom and Jamie, who have been there to encourage me and have given me some of my favourite moments over the last four years. Dedication This thesis is dedicated to my friends and family Thank you for your support Abstract Chronic pain is a condition that is thought to affect roughly 8 million people in the UK. It is classified as pain that persists for more than 6 months. Chronic pain is commonly associated with depression, insomnia, anxiety and poor quality of life. Many treatments for chronic pain are accompanied by numerous debilitating side-effects, this in combination with insufficient pain relief means that approximately 50% of patients will discontinue their treatment. Most sufferers choose to live with the pain rather than deal with numerous adverse-effects. There is a great need for new therapeutics that are specifically designed to target the underlying mechanisms of chronic pain, therefore providing safer and more effective treatments. One such mechanism is the down-regulation of strychnine-sensitive glycine receptors (SSGRs) localised in the dorsal horn. Glycinergic activity is known to be inhibitory and artificial stimulation can produce analgesia. Positive allosteric modulators acting on α1 SSGRs may able to compensate for the inhibitory glycinergic activity that is reduced in chronic pain. Previous work within the group lead into the identification of propofol analogues designed to be novel positive allosteric modulators of α1 SSGRs. Work presented in this thesis describes the generation and optimisation of these analogues with a focus of drug metabolism and pharmacokinetics. The hit to lead process has resulted in the development of a lead compound that is highly potent at the target, has excellent pharmacokinetic and safety profiles and is able to produce high levels of analgesia in an animal model of neuropathic pain. Abbreviations °C Degrees Celsius Å Angstrom(s) AC Adenylyl cyclase ACN Acrylonitrile Ala Alanine aM Attomolar AUC Area under the curve cAMP Cyclic adenosine monophosphate ClCYP Cytochrome P450 clearance Clint Intrinsic clearance ClogD Calculated distribution coefficient ClogP Calculated partition coefficient cm Centimetre(s) d. H20 Distilled water Da Daltons DMPK Drug metabolism and pharmacokinetics DMSO Dimethyl sulfoxide EC50 Half maximal effective concentration EtOAc Ethyl acetate FA Formic acid FDA Food and Drug Administration g Gram(s) G G-force GABA Gamma aminobutyric acid GABAAR Gamma aminobutyric acid (subtype A) receptor GlyR Glycine receptor HCN Hyperpolarization-activated cyclic nucleotide-gated channel HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer HLM Human liver microsomes hr(s) Hour(s) IC50 Half maximal inhibitory concentration KD Knock-down animal model Kg Kilogram(s) L Litre(s) LC Liquid Chromatography m/z Mass-to-charge ratio M+/M- Molecular ion MeOH Methanol mg Milligram(s) MgCl2 Magnesium chloride min(s) Minute(s) mL Millilitre(s) mM Millimolar mm Millimetre(s) MS Mass spectrometer mV Millivolt(s) n Sample size NADP+ Nicotinamide adenine dinucleotide phosphate NADPH Reduced nicotinamide adenine dinucleotide phosphate NaOH Sodium hydroxide NET Norepinephrine transporter ng Nanogram(s) nM Nanomolar nm Nanometre(s) NMDA N-methyl-D-aspartate OR Opioid Receptor P p-value PB Phosphate Buffer PBS Phosphate Buffer Saline PK/PD Pharmacokinetic and pharmacodynamic pKa Negative logarithm of the acid dissociation constant pM Picomolar RLM Rat liver microsomes rpm Revolutions per minute s Second(s) SEM Standard error of the mean SERT Serotonin transporter T1/2 Half-life V Voltage/Volt(s) α Alpha β Beta δ Delta κ Kappa μ Mu μg Microgram(s) μL Microliter(s) μM Micromolar Contents Declaration ........................................................................................................... 1 Acknowledgments ................................................................................................ 2 Dedication ............................................................................................................ 3 Abstract ............................................................................................................... 4 Abbreviations ...................................................................................................... 5 Contents............................................................................................................... 8 Chapter 1 : Chronic Pain ....................................................................................... 9 Chapter 2 : The Glycine Receptor as a Drug Target ............................................ 58 Chapter 3 : Lead Optimisation ........................................................................... 96 Chapter 4 : Conclusions ................................................................................... 191 Chapter 5: Experimental .......................................................................................................... 217 Appendix 231 Chapter 1 Chronic Pain Table of Contents 1.1 Pain ......................................................................................................... 11 1.1.1 Nociception ........................................................................................... 11 1.1.2 Inflammatory Pain ................................................................................. 13 1.1.3 Neuropathic Pain ................................................................................... 16 1.1.4 Chronic Pain .......................................................................................... 17 1.2 Managing Chronic Pain ............................................................................ 19 1.2.1 Antidepressants and Anticonvulsants .................................................... 19 1.2.2 Non-Steroidal Anti-inflammatory Drugs and Opioids 22 1.2.3 Adverse Effects ...................................................................................... 26 1.2.4 Gabapentin and Pregabalin ................................................................... 28 1.3 Mechanisms of Chronic Pain .................................................................... 33 1.3.1 Peripheral and Central Sensitisation ..................................................... 33 1.3.2 Disinhibition .......................................................................................... 37 1.4 Novel Therapeutic Targets ....................................................................... 41 1.4.1 M-Current ............................................................................................. 41 1.4.2 Sodium and Calcium Channels ............................................................... 43 1.4.3 Glutamate ............................................................................................. 45 1.4.4 Glycine .................................................................................................. 47 1.5 Project Aims ............................................................................................. 49 1.6 References ............................................................................................... 51 1.1 Pain 1.1.1 Nociception Pain is an unpleasant sensation that occurs when contact is made with noxious stimuli or when tissues, nerves or organs are damaged. Although uncomfortable, pain serves a protective purpose; it warns us of potential dangers and encourages us to guard injuries whilst they heal. Throughout history opium, in varying forms, has been used as a go-to for analgesia (pain relief)1. From the 1800s onwards, analgesic drugs such as morphine and aspirin have become more widely used. Improved understanding
Load more

Recommended publications
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances
    WHO/PSM/QSM/2006.3 The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances 2006 Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Medicines Policy and Standards The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
    [Show full text]
  • I Regulations
    23.2.2007 EN Official Journal of the European Union L 56/1 I (Acts adopted under the EC Treaty/Euratom Treaty whose publication is obligatory) REGULATIONS COUNCIL REGULATION (EC) No 129/2007 of 12 February 2007 providing for duty-free treatment for specified pharmaceutical active ingredients bearing an ‘international non-proprietary name’ (INN) from the World Health Organisation and specified products used for the manufacture of finished pharmaceuticals and amending Annex I to Regulation (EEC) No 2658/87 THE COUNCIL OF THE EUROPEAN UNION, (4) In the course of three such reviews it was concluded that a certain number of additional INNs and intermediates used for production and manufacture of finished pharmaceu- ticals should be granted duty-free treatment, that certain of Having regard to the Treaty establishing the European Commu- these intermediates should be transferred to the list of INNs, nity, and in particular Article 133 thereof, and that the list of specified prefixes and suffixes for salts, esters or hydrates of INNs should be expanded. Having regard to the proposal from the Commission, (5) Council Regulation (EEC) No 2658/87 of 23 July 1987 on the tariff and statistical nomenclature and on the Common Customs Tariff (1) established the Combined Nomenclature Whereas: (CN) and set out the conventional duty rates of the Common Customs Tariff. (1) In the course of the Uruguay Round negotiations, the Community and a number of countries agreed that duty- (6) Regulation (EEC) No 2658/87 should therefore be amended free treatment should be granted to pharmaceutical accordingly, products falling within the Harmonised System (HS) Chapter 30 and HS headings 2936, 2937, 2939 and 2941 as well as to designated pharmaceutical active HAS ADOPTED THIS REGULATION: ingredients bearing an ‘international non-proprietary name’ (INN) from the World Health Organisation, specified salts, esters or hydrates of such INNs, and designated inter- Article 1 mediates used for the production and manufacture of finished products.
    [Show full text]
  • Conotoxins As Tools to Understand the Physiological Function of Voltage-Gated Calcium (Cav) Channels
    marine drugs Review Conotoxins as Tools to Understand the Physiological Function of Voltage-Gated Calcium (CaV) Channels David Ramírez 1,2, Wendy Gonzalez 1,3, Rafael A. Fissore 4 and Ingrid Carvacho 5,* 1 Centro de Bioinformática y Simulación Molecular, Universidad de Talca, 3460000 Talca, Chile; [email protected] (D.R.); [email protected] (W.G.) 2 Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, 3460000 Talca, Chile 3 Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca, 3460000 Talca, Chile 4 Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA; rfi[email protected] 5 Department of Biology and Chemistry, Faculty of Basic Sciences, Universidad Católica del Maule, 3480112 Talca, Chile * Correspondence: [email protected]; Tel.: +56-71-220-3518 Received: 8 August 2017; Accepted: 4 October 2017; Published: 13 October 2017 Abstract: Voltage-gated calcium (CaV) channels are widely expressed and are essential for the completion of multiple physiological processes. Close regulation of their activity by specific inhibitors and agonists become fundamental to understand their role in cellular homeostasis as well as in human tissues and organs. CaV channels are divided into two groups depending on the membrane potential required to activate them: High-voltage activated (HVA, CaV1.1–1.4; CaV2.1–2.3) and Low-voltage activated (LVA, CaV3.1–3.3). HVA channels are highly expressed in brain (neurons), heart, and adrenal medulla (chromaffin cells), among others, and are also classified into subtypes which can be distinguished using pharmacological approaches. Cone snails are marine gastropods that capture their prey by injecting venom, “conopeptides”, which cause paralysis in a few seconds.
    [Show full text]
  • Bioactive Mimetics of Conotoxins and Other Venom Peptides
    Toxins 2015, 7, 4175-4198; doi:10.3390/toxins7104175 OPEN ACCESS toxins ISSN 2072-6651 www.mdpi.com/journal/toxins Review Bioactive Mimetics of Conotoxins and other Venom Peptides Peter J. Duggan 1,2,* and Kellie L. Tuck 3,* 1 CSIRO Manufacturing, Bag 10, Clayton South, VIC 3169, Australia 2 School of Chemical and Physical Sciences, Flinders University, Adelaide, SA 5042, Australia 3 School of Chemistry, Monash University, Clayton, VIC 3800, Australia * Authors to whom correspondence should be addressed; E-Mails: [email protected] (P.J.D.); [email protected] (K.L.T.); Tel.: +61-3-9545-2560 (P.J.D.); +61-3-9905-4510 (K.L.T.); Fax: +61-3-9905-4597 (K.L.T.). Academic Editors: Macdonald Christie and Luis M. Botana Received: 2 September 2015 / Accepted: 8 October 2015 / Published: 16 October 2015 Abstract: Ziconotide (Prialt®), a synthetic version of the peptide ω-conotoxin MVIIA found in the venom of a fish-hunting marine cone snail Conus magnus, is one of very few drugs effective in the treatment of intractable chronic pain. However, its intrathecal mode of delivery and narrow therapeutic window cause complications for patients. This review will summarize progress in the development of small molecule, non-peptidic mimics of Conotoxins and a small number of other venom peptides. This will include a description of how some of the initially designed mimics have been modified to improve their drug-like properties. Keywords: venom peptides; toxins; conotoxins; peptidomimetics; N-type calcium channel; Cav2.2 1. Introduction A wide range of species from the animal kingdom produce venom for use in capturing prey or for self-defense.
    [Show full text]
  • The Discovery and Development of Analgesics: New Mechanisms, New Modalities
    The discovery and development of analgesics: new mechanisms, new modalities Gillian Burgess, Dic Williams J Clin Invest. 2010;120(11):3753-3759. https://doi.org/10.1172/JCI43195. Review Series Despite intensive research into pain mechanisms and significant investment in research and development, the majority of analgesics available to prescribers and patients are based on mechanistic classes of compounds that have been known for many years. With considerable ingenuity and innovation, researchers continue to make the best of the mechanistic approaches available, with novel formulations, routes of administration, and combination products. Here we review some of the mechanisms and modalities of analgesics that have recently entered into clinical development, which, coupled with advances in the understanding of the pathophysiology of chronic pain, will hopefully bring the promise of new therapeutics that have the potential to provide improved pain relief for those many patients whose needs remain poorly met. Find the latest version: https://jci.me/43195/pdf Review series The discovery and development of analgesics: new mechanisms, new modalities Gillian Burgess and Dic Williams Pain Research Unit, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, United Kingdom. Despite intensive research into pain mechanisms and significant investment in research and development, the majority of analgesics available to prescribers and patients are based on mechanistic classes of compounds that have been known for many years. With considerable
    [Show full text]
  • Rodent Models of Painful Diabetic Neuropathy: What Can We Learn
    abetes & Di M f e o t a l b a o Wattiez et al., J Diabetes Metab 2012, S:5 n l r i s u m o DOI: 10.4172/2155-6156.S5-008 J Journal of Diabetes and Metabolism ISSN: 2155-6156 Review Article Open Access Rodent Models of Painful Diabetic Neuropathy: What Can We Learn from Them? Anne-Sophie Wattiez1,2#, David André Barrière1,2*#, Amandine Dupuis1,2 and Christine Courteix1,2 1Clermont Université, Université d’Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, France 2Inserm, U 1107, Neuro-Dol, F-63001 Clermont-Ferrand, France #Equal Contribution Abstract Diabetic peripheral neuropathy (DPN) is the most common clinical complication of diabetes mellitus, and can be related to type 1 as well as type 2. To date, this highly invalidating neurological impairment is insufficiently known, understood and the treatments proposed by physicians are still empirical and poorly efficient. Animal rodent modeling of clinical DPN offers a powerful tool in order to understand diabetes-mediated peripheral nerve injury. The majority of studies which have investigated DPN in rodent used the streptozotocin-induced rat model which reproduces metabolic lesional mechanisms of Type 1 Diabetes Mellitus (T1DM) and usual symptoms of evoked pain. Although the clinical relevance of this model is challenged due to 1) a high prevalence of type 2- compared to type 1-diabetes in the adult population, 2) the important alteration of the general clinical state of the animals and 3) the lack of morphological changes in peripheral nerves, many studies have contributed to a better pathophysiological and pharmacological understanding of the DPN.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • (INN) for Biological and Biotechnological Substances
    WHO/EMP/RHT/TSN/2019.1 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) 2019 WHO/EMP/RHT/TSN/2019.1 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) 2019 International Nonproprietary Names (INN) Programme Technologies Standards and Norms (TSN) Regulation of Medicines and other Health Technologies (RHT) Essential Medicines and Health Products (EMP) International Nonproprietary Names (INN) for biological and biotechnological substances (a review) FORMER DOCUMENT NUMBER: INN Working Document 05.179 © World Health Organization 2019 All rights reserved. Publications of the World Health Organization are available on the WHO website (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications –whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (www.who.int/about/licensing/copyright_form/en/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
    [Show full text]
  • Pharmacological Inhibition of Voltage-Gated Ca2+ Channels for Chronic Pain Relief
    Pharmacological Inhibition of Voltage-gated Ca2+ Channels for Chronic Pain Relief The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Lee, Seungkyu. 2013. “Pharmacological Inhibition of Voltage-gated Ca2+ Channels for Chronic Pain Relief.” Current Neuropharmacology 11 (6): 606-620. doi:10.2174/1570159X11311060005. http:// dx.doi.org/10.2174/1570159X11311060005. Published Version doi:10.2174/1570159X11311060005 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406654 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Send Orders for Reprints to [email protected] 606 Current Neuropharmacology, 2013, 11, 606-620 Pharmacological Inhibition of Voltage-gated Ca2+ Channels for Chronic Pain Relief Seungkyu Lee1,2,* 1F. M. Kirby Neurobiology Center, Children's Hospital Boston, Boston MA 02115 USA; 2Department of Neurobiology, Harvard Medical School, Boston MA 02115 USA Abstract: Chronic pain is a major therapeutic problem as the current treatment options are unsatisfactory with low efficacy and deleterious side effects. Voltage-gated Ca2+ channels (VGCCs), which are multi-complex proteins consisting of 1, , , and 2 subunits, play an important role in pain signaling. These channels are involved in neurogenic inflammation, excitability, and neurotransmitter release in nociceptors. It has been previously shown that N-type VGCCs (Cav2.2) are a major pain target. U.S. FDA approval of three Cav2.2 antagonists, gabapentin, pregabalin, and ziconotide, for chronic pain underlies the importance of this channel subtype.
    [Show full text]
  • Safavi-Hemami Et Al 2019
    Pain therapeutics from cone snail venoms From Ziconotide to novel non-opioid pathways Safavi-Hemami, Helena; Brogan, Shane E; Olivera, Baldomero M Published in: Journal of Proteomics DOI: 10.1016/j.jprot.2018.05.009 Publication date: 2019 Citation for published version (APA): Safavi-Hemami, H., Brogan, S. E., & Olivera, B. M. (2019). Pain therapeutics from cone snail venoms: From Ziconotide to novel non-opioid pathways. Journal of Proteomics, 190, 12-20. https://doi.org/10.1016/j.jprot.2018.05.009 Download date: 25. sep.. 2021 HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author J Proteomics Manuscript Author . Author manuscript; Manuscript Author available in PMC 2020 January 06. Published in final edited form as: J Proteomics. 2019 January 06; 190: 12–20. doi:10.1016/j.jprot.2018.05.009. Pain Therapeutics from Cone Snail Venoms: From Ziconotide to Novel Non-Opioid Pathways Helena Safavi-Hemami1,*, Shane E. Brogan2,3, and Baldomero M. Olivera1 1Department of Biology, University of Utah, Salt Lake City, Utah 2Department of Anesthesiology, University of Utah, Salt Lake City, Utah 3Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah Abstract There have been numerous attempts to develop non-opioid drugs for severe pain, but the vast majority of these efforts have failed. A notable exception is Ziconotide (Prialt®), approved by the FDA in 2004. In this review, we summarize the present status of Ziconotide as a therapeutic drug and introduce a wider framework: the potential of venom peptides from cone snails as a resource providing a continuous pipeline for the discovery of non-opioid pain therapeutics.
    [Show full text]
  • Pharmaabkommen A1 E
    Annex I - Pharmaceutical substances, which are free of duty_______________________________________________ Pharmaceutical substances which are Annex I free of duty CAS RN Name 136470-78-5 abacavir 129639-79-8 abafungin 792921-10-9 abagovomab 65195-55-3 abamectin 90402-40-7 abanoquil 183849-43-6 abaperidone 183552-38-7 abarelixe 332348-12-6 abatacept 143653-53-6 abciximab 111841-85-1 abecarnil 167362-48-3 abetimus 154229-19-3 abiraterone 137882-98-5 abitesartan 96566-25-5 ablukast 178535-93-8 abrineurin 91017-58-2 abunidazole 2627-69-2 acadesine 77337-76-9 acamprosate 55485-20-6 acaprazine 56180-94-0 acarbose 514-50-1 acebrochol 26976-72-7 aceburic acid 37517-30-9 acebutolol 32795-44-1 acecainide 77-66-7 acecarbromal 827-61-2 aceclidine 89796-99-6 aceclofenac 77-46-3 acedapsone 127-60-6 acediasulfone sodium 556-08-1 acedoben 80595-73-9 acefluranol 10072-48-7 acefurtiamine 70788-27-1 acefylline clofibrol 18428-63-2 acefylline piperazine 642-83-1 aceglatone 2490-97-3 aceglutamide 110042-95-0 acemannan 53164-05-9 acemetacin 131-48-6 aceneuramic acid 152-72-7 acenocoumarol 807-31-8 aceperone 61-00-7 acepromazine 13461-01-3 aceprometazine 42465-20-3 acequinoline 33665-90-6 acesulfame 118-57-0 acetaminosalol 97-44-9 acetarsol 59-66-5 acetazolamide 3031-48-9 acetergamine 299-89-8 acetiamine 2260-08-4 acetiromate 968-81-0 acetohexamide 546-88-3 acetohydroxamic acid 2751-68-0 acetophenazine 1 / 135 (As of: 1.4.2013) Annex I - Pharmaceutical substances, which are free of duty_______________________________________________ CAS RN Name 25333-77-1 acetorphine
    [Show full text]