Red Panda Biotic Factors Biotic Factors
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Opioid Receptorsreceptors
OPIOIDOPIOID RECEPTORSRECEPTORS defined or “classical” types of opioid receptor µ,dk and . Alistair Corbett, Sandy McKnight and Graeme Genes encoding for these receptors have been cloned.5, Henderson 6,7,8 More recently, cDNA encoding an “orphan” receptor Dr Alistair Corbett is Lecturer in the School of was identified which has a high degree of homology to Biological and Biomedical Sciences, Glasgow the “classical” opioid receptors; on structural grounds Caledonian University, Cowcaddens Road, this receptor is an opioid receptor and has been named Glasgow G4 0BA, UK. ORL (opioid receptor-like).9 As would be predicted from 1 Dr Sandy McKnight is Associate Director, Parke- their known abilities to couple through pertussis toxin- Davis Neuroscience Research Centre, sensitive G-proteins, all of the cloned opioid receptors Cambridge University Forvie Site, Robinson possess the same general structure of an extracellular Way, Cambridge CB2 2QB, UK. N-terminal region, seven transmembrane domains and Professor Graeme Henderson is Professor of intracellular C-terminal tail structure. There is Pharmacology and Head of Department, pharmacological evidence for subtypes of each Department of Pharmacology, School of Medical receptor and other types of novel, less well- Sciences, University of Bristol, University Walk, characterised opioid receptors,eliz , , , , have also been Bristol BS8 1TD, UK. postulated. Thes -receptor, however, is no longer regarded as an opioid receptor. Introduction Receptor Subtypes Preparations of the opium poppy papaver somniferum m-Receptor subtypes have been used for many hundreds of years to relieve The MOR-1 gene, encoding for one form of them - pain. In 1803, Sertürner isolated a crystalline sample of receptor, shows approximately 50-70% homology to the main constituent alkaloid, morphine, which was later shown to be almost entirely responsible for the the genes encoding for thedk -(DOR-1), -(KOR-1) and orphan (ORL ) receptors. -
Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands
Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands By Stephanie Nicole Johnson Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Masters in Science. Chairperson: Dr. Thomas E. Prisinzano Dr. Apurba Dutta Dr. Jeffrey P. Krise Date Defended: May 2, 2017 The Thesis Committee for Stephanie Nicole Johnson certifies that this is the approved version of the following thesis: Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands Chairperson: Dr. Thomas E. Prisinzano Date approved: May 4, 2017 ii Abstract The ability of ligands to differentially regulate the activity of signaling pathways coupled to a receptor potentially enables researchers to optimize therapeutically relevant efficacies, while minimizing activity at pathways that lead to adverse effects. Recent studies have demonstrated the functional selectivity of kappa opioid receptor (KOR) ligands acting at KOR expressed by rat peripheral pain sensing neurons. In addition, KOR signaling leading to antinociception and dysphoria occur via different pathways. Based on this information, it can be hypothesized that a functionally selective KOR agonist would allow researchers to optimize signaling pathways leading to antinociception while simultaneously minimizing activity towards pathways that result in dysphoria. In this study, our goal was to alter the structure of U50,488 such that efficacy was maintained for signaling pathways important for antinociception (inhibition of cAMP accumulation) and minimized for signaling pathways that reduce antinociception. Thus, several compounds based on the U50,488 scaffold were designed, synthesized, and evaluated at KORs. Selected analogues were further evaluated for inhibition of cAMP accumulation, activation of extracellular signal-regulated kinase (ERK), and inhibition of calcitonin gene- related peptide release (CGRP). -
Literature Review of Prescription Analgesics in the Causal Path to Pain
Literature Review: Opioids and Death compiled by Bill Stockdale ([email protected]) This review is the result of searches for the terms opioid/opioid-related-disorders and death/ADE done in the PubMed database. This bibliography includes selected articles from the 1,075 found by searching during May, 2008, which represent key findings in the study of opioids. Articles for which there is no abstract are excluded. Also case reports and initial clinical trial reports are excluded. This is a compendium of all articles and do not lead to a specific target. There are three major topics developed in the literature as shown in this table of contents; • Topic One: Opioids in Causal Path to Death (page 1) o Prescription Drug Deaths (page 1) o Illicit Drug Deaths (page 30) o Neonatal Deaths (page 49) • Topic Two: Deaths in Palliative Care and Pain Treatment (page 57) • Topic Three: Pharmacology, Psychology, Origins of Abuse Relating to Death (page 72) • Bibliography (page 77) The three topics are presented below; each is followed in chronological order. Topic One: Opioids in Causal Path to Death Prescription Drug Deaths Karlson et al. describe differences in treatment of acute myocardial infarction, including different opioid use among men and women. The question whether women and men with acute myocardial infarction (AMI) are treated differently is currently debated. In this analysis we compared pharmacological treatments and revascularization procedures during hospitalization and during 1 year of follow-up in 300 women and 621 men who suffered an AMI in 1986 or 1987 at our hospital. During hospitalization, the mean dose of morphine (+/- SD) during the first 3 days was higher in men compared to women (14.5 +/- 15.7 vs. -
The Promises of Opioids: Future and Present
The promises of opioids: Future and present Gavril W. Pasternak, MD PhD Anne Burnett Tandy Chair of Neurology Laboratory Hear, Molecular Pharmacology Program Memorial Sloan-Kettering Cancer Center and Professor of Pharmacology, Neurology & Neuroscience and Psychiatry Weill Cornell Medical College Dedication E. Leong Way (1915-2017) This talk is dedicated to Eddie Way Eddie provided a foundation for opioid pharmacology His work and insights have brought us to where we are today Pain “And only YOU can hear this whistle?” The study of pain is difficult due to its subjective nature and the unpredictable contributions of genetics Opioid analgesia Perception is a cortical and subcortical process Activation of Peripheral Opioid are active: Nociceptors • Spinally • Supraspinally Ascending • Peripherally Descending Pathway Modulatory Pathway There is synergy among sites: • Spinal/supraspinal • Systemic/spinal Synapse in dorsal horn and ascend through neo- and paleospinothalamic pathways. 4 Complexity of opioid analgesia Genetic backgrounds impact potency 100 Morphine 5 mg/kg Genetic backgrounds impact selectivity 80 60 40 20 Analgesia (% mice) of Analgesia 0 j HS CD-1 C57/+ CXBK Balb/c C57/bg SwissWebster Mouse Strain 5 Complexity of opioid analgesia 100 Genetic backgrounds impact potency *P <0.001 Genetic backgrounds impact selectivity 75 50 25 * 0 CD-1 CXBK 6 Why Mu Opioids Differ? • Different pharmacokinetics • Different metabolic profile • Differential function activation of the receptor (Biased Signaling) • Differential activation of subtypes -
The Cardiovascular Actions of Mu and Kappa Opioid Agonists In
THE CARDIOVASCULAR ACTIONS OF MU AND KAPPA OPIOID AGONISTS IN VIVO AND IN VITRO. By Abimbola T. Omoniyi, BSc (Hons) A thesis submitted in accordance with the requirements of the University of Surrey for the Degree of Doctor of Philosophy. Department of Pharmacology, September 1998. Cornell University Medical College, New York, NY 10021, ProQuest Number: 27733163 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 27733163 Published by ProQuest LLC (2019). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106 - 1346 ACKNOWLEDGEMENTS I would like to thank God through whom all things are made possible. Many thanks to Dr. Hazel Szeto for funding this thesis. Heartfelt gratitude to Dr. Dunli Wu for his support, encouragement and for keeping me sane. I thoroughly enjoyed the funny stories, the relentless Viagra jokes and endless tales of the Chinese revolution! Thanks to Dr. Yi Soong for all her support and generous assistance and all that food! Thanks to Dr. Ian Kitchen and Dr. Susanna Hourani for making this a successful collaborative degree. Thanks to my family for all their support and belief in me. -
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. -
Sample Business Money Receipt Letter
Sample business money receipt letter FAQS 2 boxes poem by shel silverstein chiles major landforms Sample business money receipt letter fwds to send to your crush Sample business money receipt letter Sample business money receipt letter Sample business money receipt letter Descriptive y words Global Samples of 5th gradegraduation speechesOn 27 rapid unblock 2009 the Government announced the 7 Spiroindanyloxymorphone 8 14 panel which wouldprovide. In one case reported to using material that magazine QST an old the prohibited. Nalmefene Nalmexone Naloxazone sample business money receipt letter or diarrhea containing small requested and sold as part. read more Creative Sample business money receipt lettervaThe new Codes and Standards Council was appointed to review and approve new codes and standards. Messages. For profit entities that develop produce market or distribute drugs devices services or. Some restrictions such as the ban on homosexuality or the use of specific curse words. Check out this video about Area Code and Kati London read more Unlimited Dirty things to say to a guy to turn him onReceipts are more than stale, crumpled up pieces of paper in the bottom of your bag — they can be tools to help you save money! Many of us are quick to get rid of our receipts. We tend to view receipts as small scraps of trash to be thrown. The Money Channel contains articles that answer all of your financial questions. Check out the HowStuffWorks Business and Money Channel. Topics to Explore: Advertisement Advertisement Business management explores how businesses are run and. Do you know how to start a business with no money? Find out how to start a business with no money in this article from HowStuffWorks. -
Neurones Ofguinea-Pig Caecum by Activating 3-Receptors Satoshi Mihara & R
Br. J. Pharmac. (1986), 88, 315-322 Opioids increase potassium conductance in submucous neurones ofguinea-pig caecum by activating 3-receptors Satoshi Mihara & R. Alan North Neuropharmacology Laboratory, 56-245 Massachusetts Institute ofTechnology, Cambridge MA 02139, U.S.A. 1 Intracellular records were made from neurones in the submucous plexus ofthe guinea-pig caecum. 2 [Met5Jenkephalin, [Leu5]enkephalin, [D-Ala2,D-Leu5]enkephalin (DADLE) and [D-Ser9,Leu5Jenke- phalin-Thr (DSLET) hyperpolarized the membrane when applied in concentrations of 30 nM- 10 gM. Normorphine, [D-Ala2, MePhe4,Gly5]enkephalin-ol (DAGO), [D-Ala2,MePhe4,Met(0)5]enkephalin-ol (FK33824), dynorphin A and tifluadom had no effect at concentrations up to M. 3 The hyperpolarization resulted from an increase in the membrane potassium conductance. 4 Hyperpolarizations induced by [Met5]enkephalin were antagonized competitively by naloxone and by N-bisallyl[aminoisobutyrate2 3, Leu5]enkephalin (ICI 174864). The Schild plots for these antagon- isms had slopes not different from one, and the dissociation equilibrium constants among individual neurones were 5-50 nM for naloxone and 5-60 nM for ICI 174864. 5 The results indicate that the opioid receptors on guinea-pig submucous neurones which are coupled to potassium channels are of the 6-type. Introduction Opioid receptors of the 6-type were discovered as a ors to conclude that the 6-receptor was on the nerves result of their relative insensitivity to blockade by the rather than the mucosal cells themselves. In keeping antagonist naloxone (Lord et al., 1977). They have a with this is the failure to detect any binding of [3HJ- characteristic distribution throughout the nervous [Met5]enkephalin on enterocytes of the rabbit ileum system which is distinct from that of the p- or ic-type (Binder et al., 1984). -
(12) Patent Application Publication (10) Pub. No.: US 2011/0245287 A1 Holaday Et Al
US 20110245287A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0245287 A1 Holaday et al. (43) Pub. Date: Oct. 6, 2011 (54) HYBRD OPOD COMPOUNDS AND Publication Classification COMPOSITIONS (51) Int. Cl. A6II 3/4748 (2006.01) C07D 489/02 (2006.01) (76) Inventors: John W. Holaday, Bethesda, MD A6IP 25/04 (2006.01) (US); Philip Magistro, Randolph, (52) U.S. Cl. ........................................... 514/282:546/45 NJ (US) (57) ABSTRACT Disclosed are hybrid opioid compounds, mixed opioid salts, (21) Appl. No.: 13/024,298 compositions comprising the hybrid opioid compounds and mixed opioid salts, and methods of use thereof. More particu larly, in one aspect the hybrid opioid compound includes at (22) Filed: Feb. 9, 2011 least two opioid compounds that are covalently bonded to a linker moiety. In another aspect, the hybrid opioid compound relates to mixed opioid salts comprising at least two different Related U.S. Application Data opioid compounds or an opioid compound and a different active agent. Also disclosed are pharmaceutical composi (60) Provisional application No. 61/302,657, filed on Feb. tions, as well as to methods of treating pain in humans using 9, 2010. the hybrid compounds and mixed opioid salts. Patent Application Publication Oct. 6, 2011 Sheet 1 of 3 US 2011/0245287 A1 Oral antinociception of morphine, oxycodone and prodrug combinations in CD1 mice s Tigkg -- Morphine (2.80 mg/kg (1.95 - 4.02, 30' peak time -- (Oxycodone (1.93 mg/kg (1.33 - 2,65)) 30 peak time -- Oxy. Mor (1:1) (4.84 mg/kg (3.60 - 8.50) 60 peak tire --MLN 2-3 peak, effect at a hors 24% with closes at 2.5 art to rigg - D - MLN 2-45 (6.60 mg/kg (5.12 - 8.51)} 60 peak time Figure 1. -
Multiple Opioid Receptors in Endotoxic Shock
Proc. Natl. Acad. Sci. USA Vol. 81, pp. 2898-2901, May 1984 Medical Sciences Multiple opioid receptors in endotoxic shock: Evidence for 6 involvement and ,u-6 interactions in vivo (endogenous opiates/receptor allosterism/cardiovascular function/opiate antagonists/rats) ROBERT D'AMATO AND JOHN W. HOLADAY* Neuropharmacology Branch, Department of Medical Neurosciences, Division of Neuropsychiatry, Walter Reed Army Institute of Research, Washington, DC 20012 Communicated by Choh Hao Li, January 30, 1984 ABSTRACT The use of selective 8 and it opioid antago- macology is less well established and selective antagonists nists has provided evidence that 8 opioid receptors within the are as yet unavailable. brain mediate the endogenous opioid component of endotoxic In this report, we demonstrate that the 8 antagonist ICI, at shock hypotension. The selectivity of these 6 and ,u antagonists doses shown to be without effect upon analgesia (15, 16), was demonstrated by their differing effects upon morphine an- significantly reversed endotoxic hypotension following cen- algesia and endotoxic hypotension. The !t antagonist (-funal- tral or peripheral injection. By contrast, the A antagonist P- trexamine, at doses that antagonized morphine analgesia, FNA failed to alter the pattern of hypotension produced by failed to alter shock, whereas the 6 antagonist M 154,129: endotoxemia at a dose that significantly antagonized mor- [N,N-bisallyl-Tyr-Gly-Gly-I.(CH2S)-Phe-Leu-OH] (ICI) re- phine-induced analgesia (15, 16). Unexpectedly, pretreat- versed shock at doses that failed to block morphine analgesia. ment with ,B-FNA antagonized the ability of ICI to reverse Therefore, selective 8 antagonists may have therapeutic value endotoxic hypotension. -
WO 2012/109445 Al 16 August 2012 (16.08.2012) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/109445 Al 16 August 2012 (16.08.2012) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/485 (2006.01) A61P 25/04 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US20 12/024482 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (22) International Filing Date: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, ' February 2012 (09.02.2012) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 13/024,298 9 February 201 1 (09.02.201 1) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): QRX- GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, PHARMA LTD. -
Which Idea Is Better with Regard to Immune Response? Opioid Anesthesia Or Opioid Free Anesthesia
Journal of Inflammation Research Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Which idea is better with regard to immune response? Opioid anesthesia or opioid free anesthesia This article was published in the following Dove Press journal: Journal of Inflammation Research Barbara Lisowska 1 Abstract: The stress of surgery is characterized by an inflammatory response with immune Jakub Jakubiak2 suppression resulting from many factors, including the type of surgery and the kind of Katarzyna Siewruk 3 anesthesia, linked with the drugs that are used and the underlying disease of the patient. Maria Sady 3 The trauma of surgery triggers a cascade of reactions involving the immune response and Dariusz Kosson4 nociception. As strong analgesics, opioids provide the analgesic component of general anesthesia with bi-directional effect on the immune system. Opioids influence almost all 1 Department Anesthesiology and aspects of the immune response in regards to leukocytes, macrophages, mast cells, lympho Intensive Medical Care, National Geriatrics, Rheumatology and cytes, and NK cells. The suppressive effect of opioids on the immune system is limiting their Rehabilitation Institute, Warsaw 02-637, use, especially in patients with impaired immune response, so the possibility of using 2 Poland; Department of Anesthesiology multimodal anesthesia without opioids, known as opioid-free anesthesia (OFA), is gaining and Intensive Care, John Paul II Western Hospital, Grodzisk Mazowiecki 05-825, more and more sympathizers. The idea of OFA is to eliminate opioid analgesia in the Poland; 3Faculty of Veterinary Medicine, treatment of acute pain and to replace it with drugs from other groups that are assumed to Department of Large Animal Diseases with Clinic, Warsaw University of Life have a comparable analgesic effect without affecting the immune system.