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Journal of Pharmacology and Experimental Therapeutics
Journal of Pharmacology and Experimental Therapeutics Molecular Determinants of Ligand Selectivity for the Human Multidrug And Toxin Extrusion Proteins, MATE1 and MATE-2K Bethzaida Astorga, Sean Ekins, Mark Morales and Stephen H Wright Department of Physiology, University of Arizona, Tucson, AZ 85724, USA (B.A., M.M., and S.H.W.) Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay-Varina NC 27526, USA (S.E.) Supplemental Table 1. Compounds selected by the common features pharmacophore after searching a database of 2690 FDA approved compounds (www.collaborativedrug.com). FitValue Common Name Indication 3.93897 PYRIMETHAMINE Antimalarial 3.3167 naloxone Antidote Naloxone Hydrochloride 3.27622 DEXMEDETOMIDINE Anxiolytic 3.2407 Chlordantoin Antifungal 3.1776 NALORPHINE Antidote Nalorphine Hydrochloride 3.15108 Perfosfamide Antineoplastic 3.11759 Cinchonidine Sulfate Antimalarial Cinchonidine 3.10352 Cinchonine Sulfate Antimalarial Cinchonine 3.07469 METHOHEXITAL Anesthetic 3.06799 PROGUANIL Antimalarial PROGUANIL HYDROCHLORIDE 100MG 3.05018 TOPIRAMATE Anticonvulsant 3.04366 MIDODRINE Antihypotensive Midodrine Hydrochloride 2.98558 Chlorbetamide Antiamebic 2.98463 TRIMETHOPRIM Antibiotic Antibacterial 2.98457 ZILEUTON Antiinflammatory 2.94205 AMINOMETRADINE Diuretic 2.89284 SCOPOLAMINE Antispasmodic ScopolamineHydrobromide 2.88791 ARTICAINE Anesthetic 2.84534 RITODRINE Tocolytic 2.82357 MITOBRONITOL Antineoplastic Mitolactol 2.81033 LORAZEPAM Anxiolytic 2.74943 ETHOHEXADIOL Insecticide 2.64902 METHOXAMINE Antihypotensive Methoxamine -
Discovery of Small Molecule and Peptide-Based Ligands for the Methyl-Lysine Binding Proteins 53Bp1 and Phf1/Phf19
DISCOVERY OF SMALL MOLECULE AND PEPTIDE-BASED LIGANDS FOR THE METHYL-LYSINE BINDING PROTEINS 53BP1 AND PHF1/PHF19 Michael Thomas Perfetti A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Division of Chemical Biology and Medicinal Chemistry in the Doctoral Program of the UNC Eshelman School of Pharmacy. Chapel Hill 2015 Approved by: Stephen Frye David Lawrence Albert Bowers Brian Strahl Greg Gang Wang Andrew Lee © 2015 Michael Thomas Perfetti ALL RIGHTS RESERVED ii ABSTRACT Michael Thomas Perfetti: Discovery of Small Molecule and Peptide-based Ligands for the Methyl-Lysine Binding Proteins 53BP1 and PHF1/PHF19 (Under the direction of Stephen V. Frye) Improving the understanding of the role of chromatin regulators in the initiation, development, and suppression of cancer and other devastating diseases is critical, as they are integral players in the regulation of DNA integrity and gene expression. Developing chemical tools for histone binding proteins that possess cellular activity will allow for further elucidation of the specific function of this class of histone regulating proteins. This research specifically targeted two different classes of Tudor domain containing histone binding proteins that are directly involved in the DNA damage response and modulation of gene transcription activities. The first methyl-lysine binding protein targeted was 53BP1, which is a DNA damage response protein. 53BP1 uses a tandem tudor domain (TTD) to recognize histone H4 dimethylated on lysine 20 (H4K20me2), a post-translational modification (PTM) induced by double-strand DNA breaks. -
Understanding Benzodiazephine Use, Abuse, and Detection
Siemens Healthcare Diagnostics, the leading clinical diagnostics company, is committed to providing clinicians with the vital information they need for the accurate diagnosis, treatment and monitoring of patients. Our comprehensive portfolio of performance-driven systems, unmatched menu offering and IT solutions, in conjunction with highly responsive service, is designed to streamline workflow, enhance operational efficiency and support improved patient care. Syva, EMIT, EMIT II, EMIT d.a.u., and all associated marks are trademarks of General Siemens Healthcare Diagnostics Inc. All Drugs other trademarks and brands are the Global Division property of their respective owners. of Abuse Siemens Healthcare Product availability may vary from Diagnostics Inc. country to country and is subject 1717 Deerfield Road to varying regulatory requirements. Deerfield, IL 60015-0778 Please contact your local USA representative for availability. www.siemens.com/diagnostics Siemens Global Headquarters Global Siemens Healthcare Headquarters Siemens AG Understanding Wittelsbacherplatz 2 Siemens AG 80333 Muenchen Healthcare Sector Germany Henkestrasse 127 Benzodiazephine Use, 91052 Erlangen Germany Abuse, and Detection Telephone: +49 9131 84 - 0 www.siemens.com/healthcare www.usa.siemens.com/diagnostics Answers for life. Order No. A91DX-0701526-UC1-4A00 | Printed in USA | © 2009 Siemens Healthcare Diagnostics Inc. Syva has been R1 R2 a leading developer N and manufacturer of AB R3 X N drugs-of-abuse tests R4 for more than 30 years. R2 C Now part of Siemens Healthcare ® Diagnostics, Syva boasts a long and Benzodiazepines have as their basic chemical structure successful track record in drugs-of-abuse a benzene ring fused to a seven-membered diazepine ring. testing, and leads the industry in the All important benzodiazepines contain a 5-aryl substituent ring (ring C) and a 1,4–diazepine ring. -
AHFS Pharmacologic-Therapeutic Classification System
AHFS Pharmacologic-Therapeutic Classification System Abacavir 48:24 - Mucolytic Agents - 382638 8:18.08.20 - HIV Nucleoside and Nucleotide Reverse Acitretin 84:92 - Skin and Mucous Membrane Agents, Abaloparatide 68:24.08 - Parathyroid Agents - 317036 Aclidinium Abatacept 12:08.08 - Antimuscarinics/Antispasmodics - 313022 92:36 - Disease-modifying Antirheumatic Drugs - Acrivastine 92:20 - Immunomodulatory Agents - 306003 4:08 - Second Generation Antihistamines - 394040 Abciximab 48:04.08 - Second Generation Antihistamines - 394040 20:12.18 - Platelet-aggregation Inhibitors - 395014 Acyclovir Abemaciclib 8:18.32 - Nucleosides and Nucleotides - 381045 10:00 - Antineoplastic Agents - 317058 84:04.06 - Antivirals - 381036 Abiraterone Adalimumab; -adaz 10:00 - Antineoplastic Agents - 311027 92:36 - Disease-modifying Antirheumatic Drugs - AbobotulinumtoxinA 56:92 - GI Drugs, Miscellaneous - 302046 92:20 - Immunomodulatory Agents - 302046 92:92 - Other Miscellaneous Therapeutic Agents - 12:20.92 - Skeletal Muscle Relaxants, Miscellaneous - Adapalene 84:92 - Skin and Mucous Membrane Agents, Acalabrutinib 10:00 - Antineoplastic Agents - 317059 Adefovir Acamprosate 8:18.32 - Nucleosides and Nucleotides - 302036 28:92 - Central Nervous System Agents, Adenosine 24:04.04.24 - Class IV Antiarrhythmics - 304010 Acarbose Adenovirus Vaccine Live Oral 68:20.02 - alpha-Glucosidase Inhibitors - 396015 80:12 - Vaccines - 315016 Acebutolol Ado-Trastuzumab 24:24 - beta-Adrenergic Blocking Agents - 387003 10:00 - Antineoplastic Agents - 313041 12:16.08.08 - Selective -
Synthesis of Isothiocyanates Using DMT/NMM/Tso− As a New Desulfurization Reagent
molecules Article Synthesis of Isothiocyanates Using DMT/NMM/TsO− as a New Desulfurization Reagent Łukasz Janczewski 1,* , Dorota Kr˛egiel 2 and Beata Kolesi ´nska 1 1 Faculty of Chemistry, Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland; [email protected] 2 Department of Environmental Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Wolczanska 171/173, 90-924 Lodz, Poland; [email protected] * Correspondence: [email protected] Abstract: Thirty-three alkyl and aryl isothiocyanates, as well as isothiocyanate derivatives from esters of coded amino acids and from esters of unnatural amino acids (6-aminocaproic, 4-(aminomethyl)benzoic, and tranexamic acids), were synthesized with satisfactory or very good yields (25–97%). Synthesis was performed in a “one-pot”, two-step procedure, in the presence of organic base (Et3N, DBU or NMM), and carbon disulfide via dithiocarbamates, with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4- methylmorpholinium toluene-4-sulfonate (DMT/NMM/TsO−) as a desulfurization reagent. For the synthesis of aliphatic and aromatic isothiocyanates, reactions were carried out in a microwave reactor, and selected alkyl isothiocyanates were also synthesized in aqueous medium with high yields (72–96%). Isothiocyanate derivatives of L- and D-amino acid methyl esters were synthesized, under conditions without microwave radiation assistance, with low racemization (er 99 > 1), and their absolute configuration was confirmed by circular dichroism. Isothiocyanate derivatives of natural and unnatural amino acids were evaluated for antibacterial activity on E. coli and S. aureus bacterial strains, where the Citation: Janczewski, Ł.; Kr˛egiel,D.; most active was ITC 9e. -
Analytical Methods for Determination of Benzodiazepines. a Short Review
Cent. Eur. J. Chem. • 12(10) • 2014 • 994-1007 DOI: 10.2478/s11532-014-0551-1 Central European Journal of Chemistry Analytical methods for determination of benzodiazepines. A short review Review Article Paulina Szatkowska1, Marcin Koba1*, Piotr Kośliński1, Jacek Wandas1, Tomasz Bączek2,3 1Department of Toxicology, Faculty of Pharmacy, Collegium Medicum of Nicolaus Copernicus University, 85-089 Bydgoszcz, Poland 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Gdańsk, 80-416 Gdańsk, Poland 3Institute of Health Sciences, Division of Human Anatomy and Physiology, Pomeranian University of Słupsk, 76-200 Słupsk, Poland Received 16 July 2013; Accepted 6 February 2014 Abstract: Benzodiazepines (BDZs) are generally commonly used as anxiolytic and/or hypnotic drugs as a ligand of the GABAA-benzodiazepine receptor. Moreover, some of benzodiazepines are widely used as an anti-depressive and sedative drugs, and also as anti-epileptic drugs and in some cases can be useful as an adjunct treatment in refractory epilepsies or anti-alcoholic therapy. High-performance liquid chromatography (HPLC) methods, thin-layer chromatography (TLC) methods, gas chromatography (GC) methods, capillary electrophoresis (CE) methods and some of spectrophotometric and spectrofluorometric methods were developed and have been extensively applied to the analysis of number of benzodiazepine derivative drugs (BDZs) providing reliable and accurate results. The available chemical methods for the determination of BDZs in biological materials and pharmaceutical formulations are reviewed in this work. Keywords: Analytical methods • Benzodiazepines • Drugs analysis • Pharmaceutical formulations © Versita Sp. z o.o. 1. Introduction and long). For this reason, an application of these drugs became broader allowing their utility to a larger extent, Benzodiazepines have been first introduced into medical and at the same time, problems related to drug abuse practice in the 60s of the last century. -
Smumedical Journal
SMU Medical Journal ISSN : 2349 – 1604 (Volume – 4, No. 1, January 2017) Review Article Indexed in SIS (USA), ASI (Germany), I2OR & i-Scholar (India), SJIF (Morocco) and Cosmos Foundation (Germany) databases. Impact Factor: 3.835 (SJIF) Analytical Aspects with Brief Overview of Depressants Sandeep Kumar1 Nand Gopal Giri2 Ashok Kumar Jaiswal3* Anil Kumar Jaiswal4 1M.Sc. (Forensic Science), LNJN NICFS, New Delhi 110085, 2Assistant Professor, Department of Chemistry, Shivaji College (University of Delhi) Raja Garden, New Delhi 110 027, 3Dept. of Forensic Medicine and toxicology, All India institute of Medical Sciences, New Delhi 110 029.4Assistant Professor, Department of Mathematics, St. Andrew’s PG College, Gorakhpur, UP. *Corresponding author Manuscript received : 30.10.2016 Manuscript accepted: 21.11.2016 Abstract Depressants are drugs that slow down the functions of the central nervous system (CNS). These drugs are used to reduce anxiety and insomnia without drowsiness. The depressants cause relaxed feeling if used in small quantity but cause unconsciousness, vomiting and even death if taken in high quantity. It affects concentration and coordination of a person by slowing down his/ her ability to respond in unexpected situations. These drugs are also attributed for their physiological and psychological effects, eventually in large dose it become lethal. The different 142 SMU Medical Journal, Volume – 4, No. – 1, January, 2017 physical and chemical features of some very often used depressants are discussed in this manuscript. Keyword: Depressant, TLC, UV spectroscopy, HPLC, GLC etc. Introduction The classical depressants are hypnotics (which induce sleep), most antianxiety medicine (diazepam or valium), muscle spasm prevent seizure, but these drugs rapidly develop dependence and tolerance which finally leads to coma and death, so use of these drugs is highly unsafe. -
The Effects of Low Dose Lysergic Acid Diethylamide Administration in a Rodent Model of Delay Discounting
Western Michigan University ScholarWorks at WMU Dissertations Graduate College 6-2020 The Effects of Low Dose Lysergic Acid Diethylamide Administration in a Rodent Model of Delay Discounting Robert J. Kohler Western Michigan University, [email protected] Follow this and additional works at: https://scholarworks.wmich.edu/dissertations Part of the Biological Psychology Commons Recommended Citation Kohler, Robert J., "The Effects of Low Dose Lysergic Acid Diethylamide Administration in a Rodent Model of Delay Discounting" (2020). Dissertations. 3565. https://scholarworks.wmich.edu/dissertations/3565 This Dissertation-Open Access is brought to you for free and open access by the Graduate College at ScholarWorks at WMU. It has been accepted for inclusion in Dissertations by an authorized administrator of ScholarWorks at WMU. For more information, please contact [email protected]. THE EFFECTS OF LOW DOSE LYSERGIC ACID DIETHYLAMIDE ADMINISTRATION IN A RODENT MODEL OF DELAY DISCOUNTING by Robert J. Kohler A dissertation submitted to the Graduate College In partial fulfillment of the requirements for the degree of Doctor of Philosophy Psychology Western Michigan University June 2020 Doctoral Committee: Lisa Baker, Ph.D., Chair Anthony DeFulio, Ph.D. Cynthia Pietras, Ph.D. John Spitsbergen, Ph.D. Copyright by Robert J. Kohler 2020 THE EFFECTS OF LOW DOSE LYSERGIC ACID DIETHYLAMIDE ADMINISTRATION IN A RODENT MODEL OF DELAY DISCOUNTING Robert J. Kohler, Ph.D. Western Michigan University, 2020 The resurgence of Lysergic Acid Diethylamide (LSD) as a therapeutic tool requires a revival in research, both basic and clinical, to bridge gaps in knowledge left from a previous generation of work. Currently, no study has been published with the intent of establishing optimal microdose concentrations of LSD in an animal model. -
The Misuse of Benzodiazepines Among High-Risk Opioid Users in Europe
EMBARGO — 7 JUNE 7. 6. 2018 UPDATED 11:30 Central European Time/CET (10:30 Western European Time/WET/Lisbon) Proof - 28 May 2018 not for circulation PERSPECTIVES ON DRUGS The misuse of benzodiazepines among high-risk opioid users in Europe Benzodiazepines are a widely prescribed I Introduction group of medicines with a range of clinical uses that include treating Benzodiazepines have a range of clinical uses and are among the most commonly prescribed medicines globally. anxiety, insomnia and managing alcohol They are useful in the short-term treatment of anxiety and withdrawal. This group of medicines is insomnia, and in managing alcohol withdrawal (Medicines often misused by high-risk opioid users, and Healthcare Products Regulatory Agency, 2015). Like all medicines, benzodiazepines can produce side effects. They and this is associated with considerable may also be misused, which we define as use without a morbidity and mortality. This paper prescription from a medical practitioner or, if prescribed, when describes the impact of benzodiazepines they are used outside accepted medical practice or guidelines. misuse on the health and treatment of While the misuse of benzodiazepines has been identified high-risk opioid users. as a concern for large groups in the general population, for example, among elderly people and women, this analysis focuses specifically on misuse among high-risk opioid users (1), a group of people among whom these medicines have been linked with severe treatment challenges and implicated in considerable numbers of drug-related deaths. It is important to stress that much benzodiazepine prescribing to high-risk drug users is done with legitimate therapeutic aims in mind. -
Specificity of the Antibody Receptor Site to D-Lysergamide
Proc. Nat. Acad. Sci. USA Vol. 68, No. 7, pp. 1483-1487, July 1971 Specificity of the Antibody Receptor Site to D-Lysergamide: Model of a Physiological Receptor for Lysergic Acid Diethylamide (molecular structure/hallucinogenic/rabbit/guinea pig/psychotomimetic) HELEN VAN VUNAKIS, JOHN T. FARROW, HILDA B. GJIKA, AND LAWRENCE LEVINE Graduate Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02154 Commnunicated by Francis 0. Schmitt, April 21, 1971 ABSTRACT Antibodies to D-lysergic acid have been amine, and NN-dimethyl-3,4,5-trimethoxyphenylethylamine produced in rabbits and guinea pigs and a radioimmuno- were the generous gifts of Dr. W. E. Scott of Hoffmann-La assay for the hapten was developed. The specificity of this Iysergamide-antilysergamide reaction was determined by Roche. DOM (2,5-dimethoxy-4-methylamphetamine) was competitive binding with unlabeled lysergic acid diethyl- given to us by Dr. S. H. Snyder of Johns Hopkins Univer- amnide (LSD), psychotomimetic drugs, neurotransmitters, sity. Sandoz Pharmaceuticals provided us with ergonovine, and other compounds with diverse structures. LSD and methylergonovine, ergosine, and ergotomine. LSD tartarate several related ergot alkaloids were potent competitors, three to seven times more potent than lysergic acid itself. powder (Sandoz Batch no. 98601) and psilocybin powder The NN-dimethyl derivatives of several compounds, in- (Sandoz Batch no. 55001) were provided by the U.S. Food and cluding tryptamine, 5-hydroxytryptamine, 4-hydroxy- Drug Administration and the National Institute of Mental tryptamine, 5-methoxytryptamine, tyramine, and mesca- Health. line, were only about ten times less effective than lysergic Psilocin was obtained by dephosphorylating psilocybin acid, even though these compounds lack some of the ring systems of lysergic acid. -
Proposed Regulation of the State Board of Pharmacy
PROPOSED REGULATION OF THE STATE BOARD OF PHARMACY LCB File No. R150-16 Workshop September 8, 2016 Explanation – Language in blue italics is new; language in red text [omitted material] is language to be omitted, and language in green text indicates prior Board-approved amendments that are in the process of being codified. AUTHORITY: §1, NRS 639.070 A REGULATION relating to controlled substances; adding certain substances to the controlled substances listed in Schedule IV; and providing other matters properly relating thereto. Section 1. NAC 453.540 is hereby amended to read as follows: NAC 453.540 Schedule IV. 1. Schedule IV consists of the drugs and other substances listed in this section, by whatever official, common, usual, chemical or trade name designated. 2. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture or preparation containing any of the following narcotic drugs, including, without limitation, their salts, calculated as the free anhydrous base of alkaloid, is hereby enumerated on schedule IV, in quantities: (a) Not more than 1 milligram of difenoxin and not less than 25 micrograms of atropine sulfate per dosage unit; or (b) Dextropropoxyphene (alpha-(+)-4-dimethylamino-1,2-diphenyl-3-methyl-2-propionoxy- butane). 3. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture or preparation which contains any quantity of the following substances, including, without limitation, their salts, isomers and salts of isomers, is hereby enumerated -
The Cardiorespiratory and Anesthetic Effects of Clinical and Supraclinical
THE CARDIORESPIRATORY AND ANESTHETIC EFFECTS OF CLINICAL AND SUPRA CLINICAL DOSES OF ALF AXALONE IN CYCLODEXTRAN IN CATS AND DOGS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Laura L. Nelson, B.S., D.V.M. * * * * * The Ohio State University 2007 Dissertation Committee: Professor Jonathan Dyce, Adviser Professor William W. Muir III Professor Shane Bateman If I have seen further, it is by standing on the shoulders of giants. lmac Ne1vton (1642-1727) Copyright by Laura L. Nelson 2007 11 ABSTRACT The anesthetic properties of steroid hormones were first identified in 1941, leading to the development of neurosteroids as clinical anesthetics. CT-1341 was developed in the early 1970’s, featuring a combination of two neurosteroids (alfaxalone and alphadolone) solubilized in Cremophor EL®, a polyethylated castor oil derivative that allows hydrophobic compounds to be carried in aqueous solution as micelles. Though also possessing anesthetic properties, alphadolone was included principally to improve the solubility of alfaxalone. CT-1341, marketed as Althesin® and Saffan®, was characterized by smooth anesthetic induction and recovery in many species, a wide therapeutic range, and no cumulative effects with repeated administration. Its cardiorespiratory effects in humans and cats were generally mild. However, it induced severe hypersensitivity reactions in dogs, with similar reactions occasionally occurring in cats and humans. The hypersensitivity reactions associated with this formulation were linked to Cremophor EL®, leading to the discontinuation of Althesin® and some other Cremophor®-containing anesthetics. More recently, alternate vehicles for hydrophobic drugs have been developed, including cyclodextrins.