Structure-Based Discovery of Selective Positive Allosteric Modulators Of
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Cell Line Descriptions Geneblazer® M1-NFAT
Version No.: GeneBLAzer ® Validation Packet Page 1 of 5 01Sep08 Optimization of the GeneBLazer ® M1-NFAT-bla Jurkat Cell Line GeneBLAzer ® M1 NFAT-bla Jurkat Cells Catalog Numbers – K1710 Cell Line Descriptions GeneBLAzer ® M1-NFAT-bla Jurkat cells contain the human Acetylcholine (muscarinic) subtype 1 receptor (M1), (Accession # NM_000738 ) stably integrated into the CellSensor ® NFAT-bla Jurkat cell line. CellSensor ® NFAT-bla Jurkat cells (Cat. no. K1671) contain a beta-lactamase (bla ) reporter gene under control of the Nuclear Factor of Activated T-cells (NFAT) response element. M1-NFAT-bla Jurkat cells are functionally validated for Z’-factor and EC 50 concentrations of carbachol (Figure 1). In addition, GeneBLAzer ® M1-NFAT-bla CHO-K1 cells have been tested for assay performance under variable conditions. Target Description Muscarinic acetylcholine receptors are members of the G protein-coupled receptor (GPCR) superfamily. Muscarinic receptors are widely distributed and mediate the actions of acetylcholine in both the CNS and peripheral tissues. Five muscarinic receptor subtypes have been identified and are referred to as M 1-M5 (1-5). The five genes that encode the muscarinic receptors all belong to the rhodopsin-line family (Family A) and share strong sequence homology but have unique regions located at the amino terminus (extracellular) and in the third intracellular loop. The M 1, M3, and M 5 receptor subtypes couple through the G q/11 class of G-proteins and activate the phopholipase C pathway. Activation of this pathway in turn leads to increases in free intracellular calcium levels as inositol triphosphate mediates release of calcium from the endoplasmic reticulum. -
Cysteinyl Leukotriene Receptor 1/2 Antagonists Nonselectively Modulate Organic Anion Transport by Multidrug Resistance Proteins (MRP1-4) S
Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2016/04/11/dmd.116.069468.DC1 1521-009X/44/6/857–866$25.00 http://dx.doi.org/10.1124/dmd.116.069468 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 44:857–866, June 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Cysteinyl Leukotriene Receptor 1/2 Antagonists Nonselectively Modulate Organic Anion Transport by Multidrug Resistance Proteins (MRP1-4) s Mark A. Csandl, Gwenaëlle Conseil, and Susan P. C. Cole Departments of Biomedical and Molecular Sciences (M.A.C., S.P.C.C.), and Pathology and Molecular Medicine (G.C., S.P.C.C.), Division of Cancer Biology and Genetics, Queen’s University Cancer Research Institute, Kingston, ON, Canada Received January 13, 2016; accepted April 7, 2016 ABSTRACT Active efflux of both drugs and organic anion metabolites is class of antagonists showed any MRP selectivity. For E217bG Downloaded from mediated by the multidrug resistance proteins (MRPs). MRP1 uptake, LTM IC50s ranged from 1.2 to 26.9 mMandweremost (ABCC1), MRP2 (ABCC2), MRP3 (ABCC3), and MRP4 (ABCC4) have comparable for MRP1 and MRP4. The LTM rank order inhibitory partially overlapping substrate specificities and all transport 17b- potencies for E217bGversusLTC4 uptake by MRP1, and E217bG estradiol 17-(b-D-glucuronide) (E217bG). The cysteinyl leukotriene versus PGE2 uptake by MRP4, were also similar. Three of four receptor 1 (CysLT1R) antagonist MK-571 inhibits all four MRP CysLT1R-selective LTMs also stimulated MRP2 (but not MRP3) homologs, but little is known about the modulatory effects of newer transport and thus exerted a concentration-dependent biphasic leukotriene modifiers (LTMs). -
Edinburgh Research Explorer
Edinburgh Research Explorer International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list Citation for published version: Davenport, AP, Alexander, SPH, Sharman, JL, Pawson, AJ, Benson, HE, Monaghan, AE, Liew, WC, Mpamhanga, CP, Bonner, TI, Neubig, RR, Pin, JP, Spedding, M & Harmar, AJ 2013, 'International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands', Pharmacological reviews, vol. 65, no. 3, pp. 967-86. https://doi.org/10.1124/pr.112.007179 Digital Object Identifier (DOI): 10.1124/pr.112.007179 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Pharmacological reviews Publisher Rights Statement: U.S. Government work not protected by U.S. copyright General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 1521-0081/65/3/967–986$25.00 http://dx.doi.org/10.1124/pr.112.007179 PHARMACOLOGICAL REVIEWS Pharmacol Rev 65:967–986, July 2013 U.S. -
The 5-HT6 Receptor Antagonist SB-271046 Selectively Enhances Excitatory Neurotransmission in the Rat Frontal Cortex and Hippocampus Lee A
The 5-HT6 Receptor Antagonist SB-271046 Selectively Enhances Excitatory Neurotransmission in the Rat Frontal Cortex and Hippocampus Lee A. Dawson, Ph.D., Huy Q. Nguyen, B.S., and Ping Li, B.S. Preclinical evidence has suggested a possible role for the 5-HT6 increases in extracellular glutamate levels in both frontal receptor in the treatment of cognitive dysfunction. However, cortex and dorsal hippocampus, respectively. These effects were currently there is little neurochemical evidence suggesting the completely attenuated by infusion of tetrodotoxin but mechanism(s) which may be involved. Using the selective unaffected by the muscarinic antagonist, atropine. Here we 5-HT6 antagonist SB-271046 and in vivo microdialysis, we demonstrate for the first time the selective enhancement of have evaluated the effects of this compound on the modulation excitatory neurotransmission by SB-271046 in those brain of basal neurotransmitter release within multiple brain regions regions implicated in cognitive and memory function, and of the freely moving rat. SB-271046 produced no change in provide mechanistic evidence in support of a possible basal levels of dopamine (DA), norepinephrine (NE) or 5-HT therapeutic role for 5-HT6 receptor antagonists in the in the striatum, frontal cortex, dorsal hippocampus or nucleus treatment of cognitive and memory dysfunction. accumbens. Similarly, this compound had no effect on [Neuropsychopharmacology 25:662–668, 2001] excitatory neurotransmission in the striatum or nucleus © 2001 American College of Neuropsychopharmacology. accumbens. Conversely, SB-271046 produced 3- and 2-fold Published by Elsevier Science Inc. KEY WORDS: 5-HT6 receptor; SB-271046; Microdialysis; sma et al. 1993; Ruat et al. -
GABA Receptors
D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43. -
(12) Patent Application Publication (10) Pub. No.: US 2006/0110449 A1 Lorber Et Al
US 200601 10449A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0110449 A1 LOrber et al. (43) Pub. Date: May 25, 2006 (54) PHARMACEUTICAL COMPOSITION Publication Classification (76) Inventors: Richard R. Lorber, Scotch Plains, NJ (US); Heribert W. Staudinger, Union, (51) Int. Cl. NJ (US); Robert E. Ward, Summit, NJ A6II 3/473 (2006.01) (US) A6II 3L/24 (2006.01) Correspondence Address: A6IR 9/20 (2006.01) SCHERING-PLOUGH CORPORATION (52) U.S. Cl. ........................... 424/464; 514/290: 514/540 PATENT DEPARTMENT (K-6-1, 1990) 2000 GALLOPNG HILL ROAD KENILWORTH, NJ 07033-0530 (US) (57) ABSTRACT (21) Appl. No.: 11/257,348 (22) Filed: Oct. 24, 2005 The present invention relates to formulations useful for Related U.S. Application Data treating respiratory disorders associated with the production of mucus glycoprotein, skin disorders, and allergic conjunc (60) Provisional application No. 60/622,507, filed on Oct. tivitis while substantially reducing adverse effects associ 27, 2004. Provisional application No. 60/621,783, ated with the administration of non-selective anti-cholin filed on Oct. 25, 2004. ergic agents and methods of use thereof. US 2006/01 10449 A1 May 25, 2006 PHARMACEUTICAL COMPOSITION example, Weinstein and Weinstein (U.S. Pat. No. 6,086,914) describe methods of treating allergic rhinitis using an anti CROSS REFERENCE TO RELATED cholinergic agent with a limited capacity to pass across lipid APPLICATION membranes, such as the blood-brain barrier, in combination with an antihistamine that is limited in both sedating and 0001. This application claims benefit of priority to U.S. -
Principle of Pharmacodynamics
Principle of pharmacodynamics Dr. M. Emamghoreishi Full Professor Department of Pharmacology Medical School Shiraz University of Medical Sciences Email:[email protected] Reference: Basic & Clinical Pharmacology: Bertrum G. Katzung and Anthony J. Treveror, 13th edition, 2015, chapter 20, p. 336-351 Learning Objectives: At the end of sessions, students should be able to: 1. Define pharmacology and explain its importance for a clinician. 2. Define ―drug receptor‖. 3. Explain the nature of drug receptors. 4. Describe other sites of drug actions. 5. Explain the drug-receptor interaction. 6. Define the terms ―affinity‖, ―intrinsic activity‖ and ―Kd‖. 7. Explain the terms ―agonist‖ and ―antagonist‖ and their different types. 8. Explain chemical and physiological antagonists. 9. Explain the differences in drug responsiveness. 10. Explain tolerance, tachyphylaxis, and overshoot. 11. Define different dose-response curves. 12. Explain the information that can be obtained from a graded dose-response curve. 13. Describe the potency and efficacy of drugs. 14. Explain shift of dose-response curves in the presence of competitive and irreversible antagonists and its importance in clinical application of antagonists. 15. Explain the information that can be obtained from a quantal dose-response curve. 16. Define the terms ED50, TD50, LD50, therapeutic index and certain safety factor. What is Pharmacology?It is defined as the study of drugs (substances used to prevent, diagnose, and treat disease). Pharmacology is the science that deals with the interactions betweena drug and the bodyor living systems. The interactions between a drug and the body are conveniently divided into two classes. The actions of the drug on the body are termed pharmacodynamicprocesses.These properties determine the group in which the drug is classified, and they play the major role in deciding whether that group is appropriate therapy for a particular symptom or disease. -
Receptor Antagonist (H RA) Shortages | May 25, 2020 2 2 2 GERD4,5 • Take This Opportunity to Determine If Continued Treatment Is Necessary
H2-receptor antagonist (H2RA) Shortages Background . 2 H2RA Alternatives . 2 Therapeutic Alternatives . 2 Adults . 2 GERD . 3 PUD . 3 Pediatrics . 3 GERD . 3 PUD . 4 Tables Table 1: Health Canada–Approved Indications of H2RAs . 2 Table 2: Oral Adult Doses of H2RAs and PPIs for GERD . 4 Table 3: Oral Adult Doses of H2RAs and PPIs for PUD . 5 Table 4: Oral Pediatric Doses of H2RAs and PPIs for GERD . 6 Table 5: Oral Pediatric Doses of H2RAs and PPIs for PUD . 7 References . 8 H2-receptor antagonist (H2RA) Shortages | May 25, 2020 1 H2-receptor antagonist (H2RA) Shortages BACKGROUND Health Canada recalls1 and manufacturer supply disruptions may be causing shortages of commonly used acid-reducing medications called histamine H2-receptor antagonists (H2RAs) . H2RAs include cimetidine, famotidine, nizatidine and ranitidine . 2 There are several Health Canada–approved indications of H2RAs (see Table 1); this document addresses the most common: gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD) . 2 TABLE 1: HEALTH CANADA–APPROVED INDICATIONS OF H2RAs H -Receptor Antagonists (H RAs) Health Canada–Approved Indications 2 2 Cimetidine Famotidine Nizatidine Ranitidine Duodenal ulcer, treatment ü ü ü ü Duodenal ulcer, prophylaxis — ü ü ü Benign gastric ulcer, treatment ü ü ü ü Gastric ulcer, prophylaxis — — — ü GERD, treatment ü ü ü ü GERD, maintenance of remission — ü — — Gastric hypersecretion,* treatment ü ü — ü Self-medication of acid indigestion, treatment and prophylaxis — ü† — ü† Acid aspiration syndrome, prophylaxis — — — ü Hemorrhage from stress ulceration or recurrent bleeding, — — — ü prophylaxis ü = Health Canada–approved indication; GERD = gastroesophageal reflux disease *For example, Zollinger-Ellison syndrome . -
Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity Kelly A
International Journal of Neuropsychopharmacology (2018) 21(10): 962–977 doi:10.1093/ijnp/pyy071 Advance Access Publication: August 6, 2018 Review review Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity Kelly A. Berg and William P. Clarke Department of Pharmacology, University of Texas Health, San Antonio, Texas. Correspondence: William P. Clarke, PhD, Department of Pharmacology, Mail Stop 7764, UT Health at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229 ([email protected]). Abstract Constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. We now know that receptors can be active without an activating ligand and thus display “constitutive” activity. As a result, a new class of ligand was discovered that can reduce the constitutive activity of a receptor. These ligands produce the opposite effect of an agonist and are called inverse agonists. The second topic discussed is functional selectivity, also commonly referred to as biased agonism. Traditional receptor theory also posited that intrinsic efficacy is a single drug property independent of the system in which the drug acts. However, we now know that a drug, acting at a single receptor subtype, can have multiple intrinsic efficacies that differ depending on which of the multiple responses coupled to a receptor is measured. -
In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs As Inverse H1 Receptor Agonists
0022-3565/07/3221-172–179$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 322, No. 1 Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics 118869/3215703 JPET 322:172–179, 2007 Printed in U.S.A. In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs as Inverse H1 Receptor Agonists R. A. Bakker,1 M. W. Nicholas,2 T. T. Smith, E. S. Burstein, U. Hacksell, H. Timmerman, R. Leurs, M. R. Brann, and D. M. Weiner Department of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.A.B., H.T., R.L.); ACADIA Pharmaceuticals Inc., San Diego, California (R.A.B., M.W.N., T.T.S., E.S.B., U.H., M.R.B., D.M.W.); and Departments of Pharmacology (M.R.B.), Neurosciences (D.M.W.), and Psychiatry (D.M.W.), University of California, San Diego, California Received January 2, 2007; accepted March 30, 2007 Downloaded from ABSTRACT The human histamine H1 receptor (H1R) is a prototypical G on this screen, we have reported on the identification of 8R- protein-coupled receptor and an important, well characterized lisuride as a potent stereospecific partial H1R agonist (Mol target for the development of antagonists to treat allergic con- Pharmacol 65:538–549, 2004). In contrast, herein we report on jpet.aspetjournals.org ditions. Many neuropsychiatric drugs are also known to po- a large number of varied clinical and chemical classes of drugs tently antagonize this receptor, underlying aspects of their side that are active in the central nervous system that display potent effect profiles. -
Biopharmacy Practice
University of Szeged Biopharmacy practice Editor: Árpád Márki, Ph.D. Authors: Árpád Márki, Ph.D. Adrienn Seres, Ph.D. Anita Sztojkov-Ivanov, Ph.D. Reviewed by: Szilárd Pál, Ph.D. Szeged, 2015. This work is supported by the European Union, co-financed by the European Social Fund, within the framework of "Coordinated, practice-oriented, student-friendly modernization of biomedical education in three Hungarian universities (Pécs, Debrecen, Szeged), with focus on the strengthening of international competitiveness" TÁMOP-4.1.1.C-13/1/KONV-2014-0001 project. The curriculum cannot be sold in any form! Contents Contents ...................................................................................................................................... 2 1. Definitions, routes of drug administration ............................................................................. 6 1.1. Definitions ....................................................................................................................... 6 1.2. Routes of drug administration ......................................................................................... 7 1.3. Questions ....................................................................................................................... 10 2. Receptors .............................................................................................................................. 11 2.1. Definitions .................................................................................................................... -
Combined Actions and Interactions of Chemicals in Mixtures the Toxicological Effects of Exposure to Mixtures of Industrial and Environmental Chemicals
Combined Actions and Interactions of Chemicals in Mixtures The Toxicological Effects of Exposure to Mixtures of Industrial and Environmental Chemicals Miljøministeriet Miljøstyrelsen Combined Actions and Interactions of Chemicals in Mixtures The Toxicological Effects of Exposure to Mixtures of Industrial and Environmental Chemicals FødevareRapport 2003:12 1st Edition, 1st Circulation, August 2003 Copyright: Danish Veterinary and Food Administration 400 copies Printing office: Schultz Price: DKK 320.- incl. VAT ISBN: 87-91399-08-4 ISSN: 1399-0829 (FødevareRapport) Id-number: 2003012 Publications costing money can be bought at book shops or: Danish State Information Centre Phone +45 7010 1881 www.danmark.dk/netboghandel The Danish Veterinary and Food Administration Mørkhøj Bygade 19, DK-2860 Søborg Tel. + 45 33 95 60 00, fax + 45 33 95 60 01 Web site: www.fdir.dk The Danish Veterinary and Food Administration is part of the Danish Ministry of Agriculture, Food and Fisheries. The Danish Veterinary and Food Administration is responsible for the administration, research and control within food and veterinary areas “from farm to fork”, as well as practical matters relating to animal protection (otherwise under the Ministry of Justice). Making of regulations, co-ordination, research and development, take place in the Administrations center in Moerkhoej. The 11 Regional Authorities handle the practical inspection of food and veterinary matters, including import/export etc. The central administration of The Danish Veterinary and Food Administration