DOCSLIB.ORG

Demonstration and Affinity Labeling of a Stereoselective Binding Site for A

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Demonstration and Affinity Labeling of a Stereoselective Binding Site for A Proc. Nati. Acad. Sci. USA Vol. 82, pp. 940-944, February 1985 Neurobiology Demonstration and affinity labeling of a stereoselective binding site for a benzomorphan opiate on acetylcholine receptor-rich membranes from Torpedo electroplaque (cholinergic receptor/ion channel/photoaffinity labeling/N-aliyl-N-normetazocine/phencyclidine) ROBERT E. OSWALD, NANCY N. PENNOW, AND JAMES T. MCLAUGHLIN Department of Pharmacology, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY 14853 Communicated by R. H. Wasserman, October 3, 1984 ABSTRACT The interaction of an optically pure benzo- Benzomorphan opiates have been shown to inhibit the morphan opiate, (-)-N-allyl-N-normetazocine [(-)-ANMC], binding of [3H]PCP to central nervous system synaptic mem- with the nicotinic acetylcholine receptor from Torpedo electro- branes (15, 16) and to modify the activity of serum cholines plaque was studied by using radioligand binding and affinity terase (17). Some opiate derivatives, in particular the benzo- labeling. The binding was complex with at least two specific morphans, can inhibit the binding of [3H]perhydrohistrioni- components having equilibrium dissociation constants of 0.3 cotoxin and [3H]PCP to the Torpedo AcChoR (18, 19). In the jiM and 2 jiM. The affinity of the higher affinity component present studies, a radioactive optically pure benzomorphan, was decreased by carbamoylcholine but not by a-bungaro- (-)-[3H]N-allyl-N-normetazocine {(-)-[3H]ANMC}, was toxin. The effect of carbamoylcholine was not blocked by a- used to measure reversible binding to and affinity labeling of bungarotoxin. In comparison, the affinity of [3Hlphencycli- the Torpedo electroplaque AcChoR. Specific binding was dine, a well-characterized ligand for a high-affinity site for shown to be complex with at least one component having noncompetitive blockers on the acetylcholine receptor, is in- lower affinity in the presence rather than the absence of cho- creased by carbamoylcholine and the increase is blocked by a- linergic effectors. Binding to the high-affinity site was inhib- bungarotoxin. The binding of (-)-[3HJANMC was inhibited ited by PCP with a mechanism that is not competitive. a- by a number of other benzomorphans, with (-) isomers being Bungarotoxin (a-BuTx) had no effect on the decrease in af- 4- to 5-fold more potent than (+) isomers. Phencyclidine inhib- finity induced by cholinergic effectors. UV-catalyzed its the binding of (-)-[3H]ANMC to its high-affinity site by a affinity labeling (20) resulted in the labeling of the 8 subunit mechanism that is not competitive. UV-catalyzed affinity la- and, in some cases, the a subunit. these results may indicate beling indicated that the high-affinity-binding site for (-)- a unique binding site for benzomorphans on the AcChoR. [3H]ANMC is at least partially associated with the 8 subunit. Tryptic degradation of the Torpedo marmorata 8 chain sug- MATERIALS AD METHODS gested that (-)-ANMC labeled a 16,000-dalton COOH-termi- AcChoR-rich membranes were prepared from the electro- nal portion of the subunit. In contrast, 5-azido-[3Hltrimethiso- plaque of Torpedo californica, Torpedo marmorata, and quin, a photoaffinity label of the high-affinity site for noncom- Torpedo nobiliana as described (21). The binding of (-)- petitive blockers, labels a 47,000-dalton N1H2-terminal [3H]ANMC was measured by either a centrifugation (10) or a fragment of the 8 subunit. These results suggest that (-)- filtration assay (22, 23) in a total volume of 125 a.l. The buff- [3HJANMC binds to sites completely distinct from the binding er used in all cases was 50 mM 3-(N-morpholino)propanesul- sites for acetylcholine. The high-affinity-binding site for (-)- fonic acid (Mops)/NaOH and } mM EGTA, pH 7.5 (Mops/ ANMC and that for phencyclidine and 5-azidotrimethisoquin EGTA). are allosterically coupled but are regulated differently and are Cross-linking of (-)-[3H]ANMC and 5-azido-[3H]trimethi- probably physically distinct. soquin (5A[3H]T) induced by irradiation with UV light was performed as described (20, 24) except that Mops/ The nicotinic acetylcholine receptor (AcChoR) from Torpe- EGTA was the buffer. Trypsin degradation was performed do electroplaque is a multisubunit protein that mediates ion as described by Wennogle et al. (25). flux across the cell membrane in response to the binding of Benzomorphan opiates (ANMC, metazocine, pentazo- acetylcholine (AcCho). The receptor complex consists of cine, cyclazocine), etorphine, naloxone, and (-)- four different subunits of 50,116 (a), 53,681 (,B), 56,279 ('y), [3H]ANMC (49.5 Ci/mmol; 1 Ci = 37 GBq) were supplied by and 57,565 (8) daltons (measured by sequence analysis; ref. the National Institute on Drug Abuse. Phenazocine, theba- 1), existing in a stoichiometry of 2:1:1:1 (2-4). These sub- ine, and oxymorphone were gifts of A. E. Jacobson (Nation- units migrate in NaDodSO4/polyacrylamide gels with appar- al Institutes of Health). A. Gero (Hanemann University) ent molecular masses of 40,000, 50,000, 60,000, and 66,000 generously supplied metazocine, pentazocine, cyclazocine, daltons, respectively. A high-affinity-binding site for AcCho 5-ethyl-2'-hydroxy-2-methyl-6,7-benzomorphan, and 5-(m- is associated, at least in part, with each of the a subunits hydroxyphenyl)-2-methylmorphan. PCP was obtained from (reviewed in ref. 5). In addition, a series of compounds, U.S. Pharmacopeial Convention (Rockville, MD), and known collectively as noncompetitive blockers, has been [3H]PCP (48 Ci/mmol), [3H]AcCho (90 mCi/mmol), and 125I1 shown to bind to the AcChoR (6-13). These compounds, labeled a-BuTx (1251-a-BuTx) were purchased from New which include phencyclidine (PCP), histrionicotoxin, chlor- England Nuclear (Boston, MA). 5A[3H]T wag a gift of J. P. promazine, and some aminated local anesthetics, bind to one Changeux (Institut Pasteur, Paris). Live T. californica were high-affinity site per AcChoR monomer (reviewed in ref. 14) purchased from Pacific Biomarine (Venice, CA), and frozen as well as to a variable number of low-affinity sites associat- T. nobiliana were purchased from Biofish Associates ed with the membrane lipids (10, 11). Abbreviations: AcCho, acetylcholine; AcChoR, AcCho receptor; The publication costs of this article were defrayed in part by page charge (-)-ANMC, (-)-N-allyl-N-normetazocine; 5A[3H]T, 5-azido- payment. This article must therefore be hereby marked "advertisement" [3H]trimethisoquin; a-BuTx, a-bungarotoxin; MPTA, [4-(N-malei- in accordance with 18 U.S.C. §1734 solely to indicate this fact. mido)phenyl]trimethylammonium; PCP, phencyclidine. 940 Downloaded by guest on September 28, 2021 Neurobiology: Oswald et aL Proc. NatL. Acad. Sci USA 82 (1985) 941 (Georgetown, MA). Ptirified T. marmorata membranes were a gift of B. Holton and A. Ribera (Institut Pasteur). RESULTS Equilibrium Bindihg of (-)-[3H]ANMC to AcChoR-Rich Membrane Fragments. As illustrated in Fig. 1, the specific binding of (-)-[3H]ANMC to AcChoR-rich membrane frag- ments from T. californica is saturable. (Identical results were obtained with T. marmorata and T. nobiliana.) The curve drawn through the experimental points represents a nonlinear least squares fit of the data to a two-site model. 0 The equilibrium dissociation constant (Kd) of the high-affini- L.O ty component is 0.36 ± 0.07 MM and that of the low-affinity ~0 component is 2.2 ± 0.4 AM. The high-affinity component o 1.0 comprises between 40% and 50% of the specific binding. The mo total concentration of sites in the preparation shown in Fig. 1 was 0.1 MM, which is within 10% of the number of AcCho binding sites measured by [3H]AcCho binding and a-BuTx binding. This suggests that two binding sites for (-)-ANMC may exist on each 250,000-dalton AcChoR monomer. Both components were lost following heating to 100'C for 3 min. Fig. 2 shows a comparison of the binding of (-)- [3H]ANMC and of [3H]PCP in the presence and absence of carbamoylcholine and a-BuTx. The affinity and number of binding sites for (-)-[3H]ANMC are unaffected by the pres- ence of a-BuTx; however, carbamoylcholine decreases the affinity of the high-affinity component without changing the number of binding sites (Fig. 2A), with an IC50 of 40 ± 8 AM. This effect is not blocked by a-BuTx. Under identical condi- Bound, cpm x 10O3 tions, a-BuTx blocks completely the agonist-induced in- FIG. 2. Binding of (-)-[3H]ANMC (A) and [3H]PCP (B) to Ac- crease in affinity for [3H]PCP and inhibits completely the ChoR-rich membrane fragments (200 nM in I251-a-BuTx sites, 0.31 binding of 125I-a-BuTx. d-Tubocurarine and decamethonium nmol of 125I-a-BuTx sites per mg of prdtein) in the presence or ab- also decrease the affinity of (-)-[3H]ANMC (IC50 values of sence of 0.2 mM carbamoylcholine (Carb) and/or 2 AM a-BuTx us- 47 ± 10 AM and 7.6 ± 1.1 MM, respectively). The effects of ing the centrifugation assay. Assays were performed following a 45- d-tubocurarine and decamethonium are not inhibited by a- min incubation at 25°C. The data are plotted a§ a Scatchard transfor- BuTx. This is in contrast to the binding of [3H]PCP, which mation of the specific binding determined following subtraction of an increased in the of nonspecific binding measured using either 0.2 mM nonradioactive shows affinity presence carbamoyl- (-)-ANMC (A) or 0.2 mM nonradioactive PCP (B). (A) The Kd for choline (EC50 = 0.15 ,uM), d-tubocurarine (EC50 = 0.08 (-)-[3H]ANMC in the presence of carbamoylcholine was 1.9 ,M, and, in the absence of carbamoylcholine, the Kd values were 0.3 AM and 2 ,M. a-BuTx had no effect on binding either in the presence or 3 A absence of carbamoylcholine. (B) The Kd for [3H]PCP was 0.11 ,M 45 S in the presence of carbamoylcholine, 1.0 AM in the absence of car- bamoylcholine, 1.6 AM in the presence of a-BuTx, and 1.1 MM in 2 0 the presence of both carbamoylcholine and a-BuTx.
Load more

Recommended publications
  • SENATE BILL No. 52
    As Amended by Senate Committee Session of 2017 SENATE BILL No. 52 By Committee on Public Health and Welfare 1-20 1 AN ACT concerning the uniform controlled substances act; relating to 2 substances included in schedules I, II and V; amending K.S.A. 2016 3 Supp. 65-4105, 65-4107 and 65-4113 and repealing the existing 4 sections. 5 6 Be it enacted by the Legislature of the State of Kansas: 7 Section 1. K.S.A. 2016 Supp. 65-4105 is hereby amended to read as 8 follows: 65-4105. (a) The controlled substances listed in this section are 9 included in schedule I and the number set forth opposite each drug or 10 substance is the DEA controlled substances code which has been assigned 11 to it. 12 (b) Any of the following opiates, including their isomers, esters, 13 ethers, salts, and salts of isomers, esters and ethers, unless specifically 14 excepted, whenever the existence of these isomers, esters, ethers and salts 15 is possible within the specific chemical designation: 16 (1) Acetyl fentanyl (N-(1-phenethylpiperidin-4-yl)- 17 N-phenylacetamide)......................................................................9821 18 (2) Acetyl-alpha-methylfentanyl (N-[1-(1-methyl-2-phenethyl)-4- 19 piperidinyl]-N-phenylacetamide)..................................................9815 20 (3) Acetylmethadol.............................................................................9601 21 (4) AH-7921 (3.4-dichloro-N-[(1- 22 dimethylaminocyclohexylmethyl]benzamide)...............................9551 23 (4)(5) Allylprodine...........................................................................9602
    [Show full text]
  • Drugs of Abuseon September Archived 13-10048 No
    U.S. DEPARTMENT OF JUSTICE DRUG ENFORCEMENT ADMINISTRATION WWW.DEA.GOV 9, 2014 on September archived 13-10048 No. v. Stewart, in U.S. cited Drugs of2011 Abuse EDITION A DEA RESOURCE GUIDE V. Narcotics WHAT ARE NARCOTICS? Also known as “opioids,” the term "narcotic" comes from the Greek word for “stupor” and originally referred to a variety of substances that dulled the senses and relieved pain. Though some people still refer to all drugs as “narcot- ics,” today “narcotic” refers to opium, opium derivatives, and their semi-synthetic substitutes. A more current term for these drugs, with less uncertainty regarding its meaning, is “opioid.” Examples include the illicit drug heroin and pharmaceutical drugs like OxyContin®, Vicodin®, codeine, morphine, methadone and fentanyl. WHAT IS THEIR ORIGIN? The poppy papaver somniferum is the source for all natural opioids, whereas synthetic opioids are made entirely in a lab and include meperidine, fentanyl, and methadone. Semi-synthetic opioids are synthesized from naturally occurring opium products, such as morphine and codeine, and include heroin, oxycodone, hydrocodone, and hydromorphone. Teens can obtain narcotics from friends, family members, medicine cabinets, pharmacies, nursing 2014 homes, hospitals, hospices, doctors, and the Internet. 9, on September archived 13-10048 No. v. Stewart, in U.S. cited What are common street names? Street names for various narcotics/opioids include: ➔ Hillbilly Heroin, Lean or Purple Drank, OC, Ox, Oxy, Oxycotton, Sippin Syrup What are their forms? Narcotics/opioids come in various forms including: ➔ T ablets, capsules, skin patches, powder, chunks in varying colors (from white to shades of brown and black), liquid form for oral use and injection, syrups, suppositories, lollipops How are they abused? ➔ Narcotics/opioids can be swallowed, smoked, sniffed, or injected.
    [Show full text]
  • Involvement of the Sigma-1 Receptor in Methamphetamine-Mediated Changes to Astrocyte Structure and Function" (2020)
    University of Kentucky UKnowledge Theses and Dissertations--Medical Sciences Medical Sciences 2020 Involvement of the Sigma-1 Receptor in Methamphetamine- Mediated Changes to Astrocyte Structure and Function Richik Neogi University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0002-8716-8812 Digital Object Identifier: https://doi.org/10.13023/etd.2020.363 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Neogi, Richik, "Involvement of the Sigma-1 Receptor in Methamphetamine-Mediated Changes to Astrocyte Structure and Function" (2020). Theses and Dissertations--Medical Sciences. 12. https://uknowledge.uky.edu/medsci_etds/12 This Master's Thesis is brought to you for free and open access by the Medical Sciences at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Medical Sciences by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known.
    [Show full text]
  • Ehealth DSI [Ehdsi V2.2.2-OR] Ehealth DSI – Master Value Set
    MTC eHealth DSI [eHDSI v2.2.2-OR] eHealth DSI – Master Value Set Catalogue Responsible : eHDSI Solution Provider PublishDate : Wed Nov 08 16:16:10 CET 2017 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 1 of 490 MTC Table of Contents epSOSActiveIngredient 4 epSOSAdministrativeGender 148 epSOSAdverseEventType 149 epSOSAllergenNoDrugs 150 epSOSBloodGroup 155 epSOSBloodPressure 156 epSOSCodeNoMedication 157 epSOSCodeProb 158 epSOSConfidentiality 159 epSOSCountry 160 epSOSDisplayLabel 167 epSOSDocumentCode 170 epSOSDoseForm 171 epSOSHealthcareProfessionalRoles 184 epSOSIllnessesandDisorders 186 epSOSLanguage 448 epSOSMedicalDevices 458 epSOSNullFavor 461 epSOSPackage 462 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 2 of 490 MTC epSOSPersonalRelationship 464 epSOSPregnancyInformation 466 epSOSProcedures 467 epSOSReactionAllergy 470 epSOSResolutionOutcome 472 epSOSRoleClass 473 epSOSRouteofAdministration 474 epSOSSections 477 epSOSSeverity 478 epSOSSocialHistory 479 epSOSStatusCode 480 epSOSSubstitutionCode 481 epSOSTelecomAddress 482 epSOSTimingEvent 483 epSOSUnits 484 epSOSUnknownInformation 487 epSOSVaccine 488 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 3 of 490 MTC epSOSActiveIngredient epSOSActiveIngredient Value Set ID 1.3.6.1.4.1.12559.11.10.1.3.1.42.24 TRANSLATIONS Code System ID Code System Version Concept Code Description (FSN) 2.16.840.1.113883.6.73 2017-01 A ALIMENTARY TRACT AND METABOLISM 2.16.840.1.113883.6.73 2017-01
    [Show full text]
  • Regulatory Strategies for Promoting the Safe Use of Prescription Opioids and the Potential Impact of Overregulation
    REGULATORY STRATEGIES FOR PROMOTING THE SAFE USE OF PRESCRIPTION OPIOIDS AND THE POTENTIAL IMPACT OF OVERREGULATION Wissenschaftliche Prüfungsarbeit zur Erlangung des Titels „Master of Drug Regulatory Affairs“ der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von Dr. Katja Bendrin aus Torgau Bonn 2020 Betreuer und Erster Referent: Dr. Birka Lehmann Zweiter Referent: Dr. Jan Heun REGULATORY STRATEGIES FOR PROMOTING THE SAFE USE OF PRESCRIPTION OPIOIDS AND THE POTENTIAL IMPACT OF OVERREGULATION Acknowledgment │ page II of VII Acknowledgment I want to thank Dr. Birka Lehmann for her willingness to supervise this work and for her support. I further thank Dr. Jan Heun for assuming the role of the second reviewer. A big thank you to the DGRA Team for the organization of the master's course and especially to Dr. Jasmin Fahnenstich for her support to find the thesis topic and supervisors. Furthermore, thank you Harald for your patient support. REGULATORY STRATEGIES FOR PROMOTING THE SAFE USE OF PRESCRIPTION OPIOIDS AND THE POTENTIAL IMPACT OF OVERREGULATION Table of Contents │ page III of VII Table of Contents 1. Scope.................................................................................................................................... 1 2. Introduction ......................................................................................................................... 2 2.1 Classification of Opioid Medicines .................................................................................................
    [Show full text]
  • The Organic Chemistry of Drug Synthesis
    The Organic Chemistry of Drug Synthesis VOLUME 2 DANIEL LEDNICER Mead Johnson and Company Evansville, Indiana LESTER A. MITSCHER The University of Kansas School of Pharmacy Department of Medicinal Chemistry Lawrence, Kansas A WILEY-INTERSCIENCE PUBLICATION JOHN WILEY AND SONS, New York • Chichester • Brisbane • Toronto Copyright © 1980 by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Sections 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc. Library of Congress Cataloging in Publication Data: Lednicer, Daniel, 1929- The organic chemistry of drug synthesis. "A Wiley-lnterscience publication." 1. Chemistry, Medical and pharmaceutical. 2. Drugs. 3. Chemistry, Organic. I. Mitscher, Lester A., joint author. II. Title. RS421 .L423 615M 91 76-28387 ISBN 0-471-04392-3 Printed in the United States of America 10 987654321 It is our pleasure again to dedicate a book to our helpmeets: Beryle and Betty. "Has it ever occurred to you that medicinal chemists are just like compulsive gamblers: the next compound will be the real winner." R. L. Clark at the 16th National Medicinal Chemistry Symposium, June, 1978. vii Preface The reception accorded "Organic Chemistry of Drug Synthesis11 seems to us to indicate widespread interest in the organic chemistry involved in the search for new pharmaceutical agents. We are only too aware of the fact that the book deals with a limited segment of the field; the earlier volume cannot be considered either comprehensive or completely up to date.
    [Show full text]
  • Outline for Controlled Substances Program
    Environmental Health and Safety Controlled Substances Program Date of Issuance: Review Date: 10/1/2019 (no changes) 10/01/2018 Revision Number: Initial Prepared by: EH&S Table of Contents HEADINGS Introduction Applicability Responsibilities Registration Requirements Authorized Use Ordering/Purchasing Administering and Dispensing Inventory Procedures (Continuing Records) Security Disposal FORMS: Registering or renewing a DEA or state license (CMU) Controlled Substances Authorized users list (CMU) Employee questionnaire for those with access to controlled substances (CMU) Record of Form 222 use (Order form) (CMU) Records of Controlled Substance Purchases (CMU) Record of Controlled Substance Administering and dispensing (CMU) Controlled Substance Physical Inventory (CMU) DEA Registration of Persons doing research or analysis (Form 225) DEA Registration of Dispensers (Form 224) DEA Registration Instructional (Form 224 and 226 to renew) DEA Report of loss or theft (Form 106) DEA Report of drugs surrendered (From 41) DEA SCHEDULES: Schedule I Schedule II Schedule III Schedule IV Schedule V INTRODUCTION State and Federal regulations have been promulgated concerning the use and handling of US Department of Justice Drug Enforcement Administration (DEA) controlled substances. These regulations are in place to address materials which are or have the potential to be addictive or habit forming. These substances have been categorized into “schedules” that have been created by the DEA to reflect their level of concern. The “Carnegie Mellon University DEA Controlled Substances Program” is intended to ensure that Carnegie Mellon University is in compliance with our regulatory requirements. Required activities under the DEA include: 1. Registration of your work with the DEA and with Carnegie Mellon’s Department of Environmental Health and Safety (EH&S).
    [Show full text]
  • Recreational Marijuana Legalization and Prescription Opioids Received by Medicaid Enrollees T ⁎ Yuyan Shia, , Di Lianga, Yuhua Baob, Ruopeng Anc, Mark S
    Drug and Alcohol Dependence 194 (2019) 13–19 Contents lists available at ScienceDirect Drug and Alcohol Dependence journal homepage: www.elsevier.com/locate/drugalcdep Full length article Recreational marijuana legalization and prescription opioids received by Medicaid enrollees T ⁎ Yuyan Shia, , Di Lianga, Yuhua Baob, Ruopeng Anc, Mark S. Wallaced, Igor Grante a Department of Family Medicine and Public Health, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA b Department of Healthcare Policy and Research, Weill Cornell Medical College, 425 E 61stSt., New York, NY, 10065, USA c Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, 1206 S 4thSt, Champaign, IL, 61820, USA d Department of Anesthesiology, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA e Department of Psychiatry, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA ARTICLE INFO ABSTRACT Keywords: Objectives: Medical marijuana use may substitute prescription opioid use, whereas nonmedical marijuana use Marijuana may be a risk factor of prescription opioid misuse. This study examined the associations between recreational Opioid marijuana legalization and prescription opioids received by Medicaid enrollees. Recreational marijuana legalization Methods: State-level quarterly prescription drug utilization records for Medicaid enrollees during 2010–2017 Opioid prescription were obtained from Medicaid State Drug Utilization Data. The primary outcome, opioid prescriptions received, Medicaid was measured in three population-adjusted variables: number of opioid prescriptions, total doses of opioid prescriptions in morphine milligram equivalents, and related Medicaid spending, per quarter per 100 enrollees. Two difference-in-difference models were used to test the associations: eight states and DC that legalized re- creational marijuana during the study period were first compared among themselves, then compared to six states with medical marijuana legalized before the study period.
    [Show full text]
  • The Organic Chemistry of Drug Synthesis
    THE ORGANIC CHEMISTRY OF DRUG SYNTHESIS VOLUME 3 DANIEL LEDNICER Analytical Bio-Chemistry Laboratories, Inc. Columbia, Missouri LESTER A. MITSCHER The University of Kansas School of Pharmacy Department of Medicinal Chemistry Lawrence, Kansas A WILEY-INTERSCIENCE PUBLICATION JOHN WILEY AND SONS New York • Chlchester • Brisbane * Toronto • Singapore Copyright © 1984 by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Section 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc. Library of Congress Cataloging In Publication Data: (Revised for volume 3) Lednicer, Daniel, 1929- The organic chemistry of drug synthesis. "A Wiley-lnterscience publication." Includes bibliographical references and index. 1. Chemistry, Pharmaceutical. 2. Drugs. 3. Chemistry, Organic—Synthesis. I. Mitscher, Lester A., joint author. II. Title. [DNLM 1. Chemistry, Organic. 2. Chemistry, Pharmaceutical. 3. Drugs—Chemical synthesis. QV 744 L473o 1977] RS403.L38 615M9 76-28387 ISBN 0-471-09250-9 (v. 3) Printed in the United States of America 10 907654321 With great pleasure we dedicate this book, too, to our wives, Beryle and Betty. The great tragedy of Science is the slaying of a beautiful hypothesis by an ugly fact. Thomas H. Huxley, "Biogenesis and Abiogenisis" Preface Ihe first volume in this series represented the launching of a trial balloon on the part of the authors. In the first place, wo were not entirely convinced that contemporary medicinal (hemistry could in fact be organized coherently on the basis of organic chemistry.
    [Show full text]
  • 19 CSR 30-1.042 Inventory Requirements
    Rules of Department of Health and Senior Services Division 30—Division of Regulation and Licensure Chapter 1—Controlled Substances Title Page 19 CSR 30-1.002 Schedules of Controlled Substances .........................................................3 19 CSR 30-1.004 List of Excepted Substances.................................................................13 19 CSR 30-1.006 List of Exempt Anabolic Steroid Products................................................13 19 CSR 30-1.008 List of Excluded Veterinary Anabolic Steroid Implant Products......................14 19 CSR 30-1.010 Schedules of Controlled Substances (Rescinded November 30, 2000)...............14 19 CSR 30-1.011 Definitions......................................................................................15 19 CSR 30-1.013 Miscellaneous Fees ...........................................................................16 19 CSR 30-1.015 Registrations and Fees........................................................................16 19 CSR 30-1.017 Registration Process ..........................................................................16 19 CSR 30-1.019 Registration Location.........................................................................19 19 CSR 30-1.020 List of Excepted Substances (Rescinded November 30, 2000)........................19 19 CSR 30-1.023 Registration Changes .........................................................................19 19 CSR 30-1.025 List of Exempt Anabolic Steroid Products (Rescinded November 30, 2000).......20 19 CSR 30-1.026
    [Show full text]
  • Tennessee Drug Statutes (Listed in Numerical Order)
    Tennessee Drug Statutes (listed in numerical order) 39-17-405. Criteria for Schedule I. • The commissioner of mental health and substance abuse services, upon the agreement of the commissioner of health, shall place a substance in Schedule I upon finding that the substance has: o (1) High potential for abuse; and o (2) No accepted medical use in treatment in the United States or lacks accepted safety for use in treatment under medical supervision. 39-17-406. Controlled substances in Schedule I. • (a) Schedule I consists of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. • (b) Opiates, unless specifically excepted or unless listed in another schedule, means any of the following opiates, including their isomers, esters, ethers, salts and salts of isomers, esters, and ethers, whenever the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation. For the purposes of subdivision (b)(34) only, the term isomer includes the optical and geometric isomers. o (1) Acetyl-alpha-methylfentanyl (N-[1-(1-methyl-2-phenethyl)-4- piperidinyl]-N-phenylacetamide); o (2) Acetylmethadol; o (3) Allylprodine; o (4) Alphacetylmethadol (except levo-alphacetylmethadol also known as levo-alpha-acetylmethadol; levomethadyl acetate; or LAAM); o (5) Alphameprodine; o (6) Alphamethadol; o (7) Alpha-methylfentanyl (N-[1-(alpha-methyl-beta-phenyl)ethyl-4- piperidyl]propionanilide; 1-(1-methyl-2-phenylethyl)-4-(N- propanilido)piperidine;
    [Show full text]
  • TALWIN Nx Is an Analgesic for Oral Administration
    NDA 018733/S-015 Page 4 TALWIN® Nx CIV pentazocine hydrochloride and naloxone hydrochloride, USP Analgesic for Oral Use Only WARNING: TALWIN® Nx is intended for oral use only. Severe, potentially lethal, reactions may result from misuse of TALWIN® Nx by injection either alone or in combination with other substances. (See DRUG ABUSE AND DEPENDENCE section.) DESCRIPTION TALWIN Nx (pentazocine and naloxone hydrochlorides, USP) contains pentazocine hydrochloride, USP, equivalent to 50 mg base and is a member of the benzazocine series (also known as the benzomorphan series), and naloxone hydrochloride, USP, equivalent to 0.5 mg base. TALWIN Nx is an analgesic for oral administration. Chemically, pentazocine hydrochloride is (2R*,6R*,11R*)-1,2,3,4,5,6-Hexahydro-6,11­ dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride, a white, crystalline substance soluble in acidic aqueous solutions, and has the following structural formula: C19H27NO·HCl M.W. 321.88 Chemically, naloxone hydrochloride is Morphinan-6-one,4,5-epoxy-3,14-dihydroxy-17-(2­ propenyl)-, hydrochloride, (5α)-. It is a slightly off-white powder, and is soluble in water and dilute acids, and has the following structural formula: Reference ID: 2909136 NDA 018733/S-015 Page 5 C19H21NO4·HCl M.W.=363.84 Inactive Ingredients: Colloidal Silicon Dioxide, Dibasic Calcium Phosphate, D&C Yellow #10, FD&C Yellow #6, Magnesium Stearate, Microcrystalline Cellulose, Sodium Lauryl Sulfate, Starch. CLINICAL PHARMACOLOGY Pentazocine is a Schedule IV opioid analgesic which when administered orally in a 50 mg dose appears equivalent in analgesic effect to 60 mg of codeine.
    [Show full text]