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(12) Patent Application Publication (10) Pub. No.: US 2004/0224020 A1 Schoenhard (43) Pub
US 2004O224020A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0224020 A1 Schoenhard (43) Pub. Date: Nov. 11, 2004 (54) ORAL DOSAGE FORMS WITH (22) Filed: Dec. 18, 2003 THERAPEUTICALLY ACTIVE AGENTS IN CONTROLLED RELEASE CORES AND Related U.S. Application Data IMMEDIATE RELEASE GELATIN CAPSULE COATS (60) Provisional application No. 60/434,839, filed on Dec. 18, 2002. (76) Inventor: Grant L. Schoenhard, San Carlos, CA (US) Publication Classification Correspondence Address: (51) Int. Cl. ................................................... A61K 9/24 Janet M. McNicholas (52) U.S. Cl. .............................................................. 424/471 McAndrews, Held & Malloy, Ltd. 34th Floor (57) ABSTRACT 500 W. Madison Street Chicago, IL 60661 (US) The present invention relates to oral dosage form with active agents in controlled release cores and in immediate release (21) Appl. No.: 10/742,672 gelatin capsule coats. Patent Application Publication Nov. 11, 2004 Sheet 1 of 3 US 2004/0224020 A1 r N 2.S Hr s Patent Application Publication Nov. 11, 2004 Sheet 2 of 3 US 2004/0224020 A1 r CN -8 e N va N . t Cd NOLLYRILNONOO Patent Application Publication Nov. 11, 2004 Sheet 3 of 3 US 2004/0224020 A1 US 2004/0224020 A1 Nov. 11, 2004 ORAL DOSAGE FORMS WITH released formulations, a long t is particularly disadvan THERAPEUTICALLY ACTIVE AGENTS IN tageous to patients Seeking urgent treatment and to maintain CONTROLLED RELEASE CORES AND MEC levels. A second difference in the pharmacokinetic IMMEDIATE RELEASE GELATIN CAPSULE profiles of controlled release in comparison to immediate COATS release drug formulations is that the duration of Sustained plasma levels is longer in the controlled release formula CROSS REFERENCED APPLICATIONS tions. -
INVESTIGATION of NATURAL PRODUCT SCAFFOLDS for the DEVELOPMENT of OPIOID RECEPTOR LIGANDS by Katherine M
INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS By Katherine M. Prevatt-Smith 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 Doctor of Philosophy. _________________________________ Chairperson: Dr. Thomas E. Prisinzano _________________________________ Dr. Brian S. J. Blagg _________________________________ Dr. Michael F. Rafferty _________________________________ Dr. Paul R. Hanson _________________________________ Dr. Susan M. Lunte Date Defended: July 18, 2012 The Dissertation Committee for Katherine M. Prevatt-Smith certifies that this is the approved version of the following dissertation: INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS _________________________________ Chairperson: Dr. Thomas E. Prisinzano Date approved: July 18, 2012 ii ABSTRACT Kappa opioid (KOP) receptors have been suggested as an alternative target to the mu opioid (MOP) receptor for the treatment of pain because KOP activation is associated with fewer negative side-effects (respiratory depression, constipation, tolerance, and dependence). The KOP receptor has also been implicated in several abuse-related effects in the central nervous system (CNS). KOP ligands have been investigated as pharmacotherapies for drug abuse; KOP agonists have been shown to modulate dopamine concentrations in the CNS as well as attenuate the self-administration of cocaine in a variety of species, and KOP antagonists have potential in the treatment of relapse. One drawback of current opioid ligand investigation is that many compounds are based on the morphine scaffold and thus have similar properties, both positive and negative, to the parent molecule. Thus there is increasing need to discover new chemical scaffolds with opioid receptor activity. -
Augmentation of Morphine-Induced Sensitization but Reduction in Morphine Tolerance and Reward in Delta-Opioid Receptor Knockout Mice
Neuropsychopharmacology (2009) 34, 887–898 & 2009 Nature Publishing Group All rights reserved 0893-133X/09 $32.00 www.neuropsychopharmacology.org Augmentation of Morphine-Induced Sensitization but Reduction in Morphine Tolerance and Reward in Delta-Opioid Receptor Knockout Mice ,1 1 VI Chefer* and TS Shippenberg 1Integrative Neuroscience Section, Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA Studies in experimental animals have shown that individuals exhibiting enhanced sensitivity to the locomotor-activating and rewarding properties of drugs of abuse are at increased risk for the development of compulsive drug-seeking behavior. The purpose of the present study was to assess the effect of constitutive deletion of delta-opioid receptors (DOPr) on the rewarding properties of morphine as well as on the development of sensitization and tolerance to the locomotor-activating effects of morphine. Locomotor activity testing revealed that mice lacking DOPr exhibit an augmentation of context-dependent sensitization following repeated, alternate injections of morphine (20 mg/kg; s.c.; 5 days). In contrast, the development of tolerance to the locomotor-activating effects of morphine following chronic morphine administration (morphine pellet: 25 mg: 3 days) is reduced relative to WT mice. The conditioned rewarding effects of morphine were reduced significantly in DOPrKO mice as compared to WT controls. Similar findings were obtained in response to pharmacological inactivation of DOPr in WT mice, indicating that observed effects are not due to developmental adaptations that occur as a consequence of constitutive deletion of DOPr. Together, these findings indicate that the endogenous DOPr system is recruited in response to both repeated and chronic morphine administration and that this recruitment serves an essential function in the development of tolerance, behavioral sensitization, and the conditioning of opiate reward. -
Design and Synthesis of Cyclic Analogs of the Kappa Opioid Receptor Antagonist Arodyn
Design and synthesis of cyclic analogs of the kappa opioid receptor antagonist arodyn By © 2018 Solomon Aguta Gisemba 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 Doctor of Philosophy. Chair: Dr. Blake Peterson Co-Chair: Dr. Jane Aldrich Dr. Michael Rafferty Dr. Teruna Siahaan Dr. Thomas Tolbert Date Defended: 18 April 2018 The dissertation committee for Solomon Aguta Gisemba certifies that this is the approved version of the following dissertation: Design and synthesis of cyclic analogs of the kappa opioid receptor antagonist arodyn Chair: Dr. Blake Peterson Co-Chair: Dr. Jane Aldrich Date Approved: 10 June 2018 ii Abstract Opioid receptors are important therapeutic targets for mood disorders and pain. Kappa opioid receptor (KOR) antagonists have recently shown potential for treating drug addiction and 1,2,3 4 8 depression. Arodyn (Ac[Phe ,Arg ,D-Ala ]Dyn A(1-11)-NH2), an acetylated dynorphin A (Dyn A) analog, has demonstrated potent and selective KOR antagonism, but can be rapidly metabolized by proteases. Cyclization of arodyn could enhance metabolic stability and potentially stabilize the bioactive conformation to give potent and selective analogs. Accordingly, novel cyclization strategies utilizing ring closing metathesis (RCM) were pursued. However, side reactions involving olefin isomerization of O-allyl groups limited the scope of the RCM reactions, and their use to explore structure-activity relationships of aromatic residues. Here we developed synthetic methodology in a model dipeptide study to facilitate RCM involving Tyr(All) residues. Optimized conditions that included microwave heating and the use of isomerization suppressants were applied to the synthesis of cyclic arodyn analogs. -
(12) United States Patent (10) Patent No.: US 9,687,445 B2 Li (45) Date of Patent: Jun
USOO9687445B2 (12) United States Patent (10) Patent No.: US 9,687,445 B2 Li (45) Date of Patent: Jun. 27, 2017 (54) ORAL FILM CONTAINING OPIATE (56) References Cited ENTERC-RELEASE BEADS U.S. PATENT DOCUMENTS (75) Inventor: Michael Hsin Chwen Li, Warren, NJ 7,871,645 B2 1/2011 Hall et al. (US) 2010/0285.130 A1* 11/2010 Sanghvi ........................ 424/484 2011 0033541 A1 2/2011 Myers et al. 2011/0195989 A1* 8, 2011 Rudnic et al. ................ 514,282 (73) Assignee: LTS Lohmann Therapie-Systeme AG, Andernach (DE) FOREIGN PATENT DOCUMENTS CN 101703,777 A 2, 2001 (*) Notice: Subject to any disclaimer, the term of this DE 10 2006 O27 796 A1 12/2007 patent is extended or adjusted under 35 WO WOOO,32255 A1 6, 2000 U.S.C. 154(b) by 338 days. WO WO O1/378O8 A1 5, 2001 WO WO 2007 144080 A2 12/2007 (21) Appl. No.: 13/445,716 (Continued) OTHER PUBLICATIONS (22) Filed: Apr. 12, 2012 Pharmaceutics, edited by Cui Fude, the fifth edition, People's Medical Publishing House, Feb. 29, 2004, pp. 156-157. (65) Prior Publication Data Primary Examiner — Bethany Barham US 2013/0273.162 A1 Oct. 17, 2013 Assistant Examiner — Barbara Frazier (74) Attorney, Agent, or Firm — ProPat, L.L.C. (51) Int. Cl. (57) ABSTRACT A6 IK 9/00 (2006.01) A control release and abuse-resistant opiate drug delivery A6 IK 47/38 (2006.01) oral wafer or edible oral film dosage to treat pain and A6 IK 47/32 (2006.01) substance abuse is provided. -
In Vivoactivation of a Mutantμ-Opioid Receptor by Naltrexone Produces A
The Journal of Neuroscience, March 23, 2005 • 25(12):3229–3233 • 3229 Brief Communication In Vivo Activation of a Mutant -Opioid Receptor by Naltrexone Produces a Potent Analgesic Effect But No Tolerance: Role of -Receptor Activation and ␦-Receptor Blockade in Morphine Tolerance Sabita Roy, Xiaohong Guo, Jennifer Kelschenbach, Yuxiu Liu, and Horace H. Loh Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455 Opioid analgesics are the standard therapeutic agents for the treatment of pain, but their prolonged use is limited because of the development of tolerance and dependence. Recently, we reported the development of a -opioid receptor knock-in (KI) mouse in which the -opioid receptor was replaced by a mutant receptor (S196A) using a homologous recombination gene-targeting strategy. In these animals, the opioid antagonist naltrexone elicited antinociceptive effects similar to those of partial agonists acting in wild-type (WT) mice; however, development of tolerance and physical dependence were greatly reduced. In this study, we test the hypothesis that the failure of naltrexone to produce tolerance in these KI mice is attributable to its simultaneous inhibition of ␦-opioid receptors and activation of -opioid receptors. Simultaneous implantation of a morphine pellet and continuous infusion of the ␦-opioid receptor antagonist naltrindole prevented tolerance development to morphine in both WT and KI animals. Moreover, administration of SNC-80 [(ϩ)-4-[(␣R)-␣-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide], a ␦ agonist, in the naltrexone- pelleted KI animals resulted in a dose-dependent induction in tolerance development to both morphine- and naltrexone-induced anal- gesia. We conclude that although simultaneous activation of both - and ␦-opioid receptors results in tolerance development, -opioid receptor activation in conjunction with ␦-opioid receptor blockade significantly attenuates the development of tolerance. -
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. -
4 Supplementary File
Supplemental Material for High-throughput screening discovers anti-fibrotic properties of Haloperidol by hindering myofibroblast activation Michael Rehman1, Simone Vodret1, Luca Braga2, Corrado Guarnaccia3, Fulvio Celsi4, Giulia Rossetti5, Valentina Martinelli2, Tiziana Battini1, Carlin Long2, Kristina Vukusic1, Tea Kocijan1, Chiara Collesi2,6, Nadja Ring1, Natasa Skoko3, Mauro Giacca2,6, Giannino Del Sal7,8, Marco Confalonieri6, Marcello Raspa9, Alessandro Marcello10, Michael P. Myers11, Sergio Crovella3, Paolo Carloni5, Serena Zacchigna1,6 1Cardiovascular Biology, 2Molecular Medicine, 3Biotechnology Development, 10Molecular Virology, and 11Protein Networks Laboratories, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 34149, Trieste, Italy 4Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy 5Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany 6Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy 7National Laboratory CIB, Area Science Park Padriciano, Trieste, 34149, Italy 8Department of Life Sciences, University of Trieste, Trieste, 34127, Italy 9Consiglio Nazionale delle Ricerche (IBCN), CNR-Campus International Development (EMMA- INFRAFRONTIER-IMPC), Rome, Italy This PDF file includes: Supplementary Methods Supplementary References Supplementary Figures with legends 1 – 18 Supplementary Tables with legends 1 – 5 Supplementary Movie legends 1, 2 Supplementary Methods Cell culture Primary murine fibroblasts were isolated from skin, lung, kidney and hearts of adult CD1, C57BL/6 or aSMA-RFP/COLL-EGFP mice (1) by mechanical and enzymatic tissue digestion. Briefly, tissue was chopped in small chunks that were digested using a mixture of enzymes (Miltenyi Biotec, 130- 098-305) for 1 hour at 37°C with mechanical dissociation followed by filtration through a 70 µm cell strainer and centrifugation. -
Differential Effects of Novel Kappa Opioid Receptor Antagonists on Dopamine Neurons Using Acute Brain Slice Electrophysiology
PLOS ONE RESEARCH ARTICLE Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology 1 2 2 2 Elyssa B. MargolisID *, Tanya L. Wallace , Lori Jean Van Orden , William J. Martin 1 Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States of America, 2 BlackThorn Therapeutics, San Francisco, CA, United States of America a1111111111 a1111111111 * [email protected] a1111111111 a1111111111 a1111111111 Abstract Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contribut- OPEN ACCESS ing to aversive responses (Margolis et al. 2003, 2006); therefore, selective KOR antagonists Citation: Margolis EB, Wallace TL, Van Orden LJ, represent a novel therapeutic approach to restore circuit function. We used whole cell Martin WJ (2020) Differential effects of novel kappa opioid receptor antagonists on dopamine electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four neurons using acute brain slice electrophysiology. novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. PLoS ONE 15(12): e0232864. https://doi.org/ Each compound concentration-dependently reduced the outward current induced by the 10.1371/journal.pone.0232864 KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 Editor: Bradley Taylor, University of Pittsburgh, currents (IC50 = 1.2 ± 0.9 and 1.2 ± 1.3 nM, respectively). JNJ-67953964 showed an IC50 of UNITED STATES 3.0 ± 4.6 nM. -
Constitutive Activity of the Δ-Opioid Receptor Expressed in C6 Glioma Cells
British Journal of Pharmacology (1999) 128, 556 ± 562 ã 1999 Stockton Press All rights reserved 0007 ± 1188/99 $15.00 http://www.stockton-press.co.uk/bjp Constitutive activity of the d-opioid receptor expressed in C6 glioma cells: identi®cation of non-peptide d-inverse agonists 1Claire L. Neilan, 3Huda Akil, 1,2James H. Woods & *,1John R. Traynor 1Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, Ann Arbor, Michigan, MI 48109-0632, USA; 2Department of Psychology, University of Michigan Medical School, 1301 MSRB III, Ann Arbor, Michigan, MI 48109-0632, USA and 3Mental Health Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, MI 48109-0720, USA 1 G-protein coupled receptors can exhibit constitutive activity resulting in the formation of active ternary complexes in the absence of an agonist. In this study we have investigated constitutive activity in C6 glioma cells expressing either the cloned d-(OP1) receptor (C6d), or the cloned m-(OP3) opioid receptor (C6m). 2 Constitutive activity was measured in the absence of Na+ ions to provide an increased signal. The degree of constitutive activity was de®ned as the level of [35S]-GTPgS binding that could be inhibited by pre-treatment with pertussis toxin (PTX). In C6d cells the level of basal [35S]-GTPgS binding was reduced by 51.9+6.1 fmols mg71 protein, whereas in C6m and C6 wild-type cells treatment with PTX reduced basal [35S]-GTPgS binding by only 10.0+3.5 and 8.6+3.1 fmols mg71 protein respectively. 3 The d-antagonists N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864), 7-benzylidenenaltrexone (BNTX) and naltriben (NTB), in addition to clocinnamox (C-CAM), acted as d-opioid receptor inverse agonists. -
Adrenoceptor (1) Antibiotic (2) Cyclic Nucleotide (4) Dopamine (5) Hormone (6) Serotonin (8) Other (9) Phosphorylation (7) Ca2+
Supplementary Fig. 1 Lifespan-extending compounds can show structural similarity or have common substructures. Cl NO2 H doxycycline (2) N N NH 2 O H O H O O H O O O O O H O NH NH Cl O O 2 N N guanfacine (1) O H N N H H H nitrendipine (3) S Cl N H promethazine (9) NO2 F N NH2 F N demeclocycline (2) O H O O H O O F N NH O O H O O Cl S N NH N guanabenz (1) O O 2 fluphenthixol (5) Br CN O H N H N nicardipine (3) S N H Cl O H N N propionylpromazine (5) O O H O H O O H O O O H Cl N S Br LFM−A13 (7) NH2 S S O H H H chlorprothixene (5) thioridazine (5) N N O H minocycline (2) HO S O β-estradiol (6) O H H N H N H O H O danazol (6) N N cyproterone (6) H N H O H O methylergonovine (5) HO H pergolide (5) O N O O O N O HN O O H O N N H 3C H H O O H Cl H O H C H 3 O H N N H N H N H H O metergoline (8) dihydroergocristine (5) Cortexolone (5) HO O N (R,R)−cis−Diethyltetrahydro−2,8−chrysenediol (6) O H O H N O vincristine (9) N H N HN H O H H N H O N N N N O N H O O O N N dihydroergotamine (8) H O Cl O H O H O nortriptyline (1) S O mianserin (8) octoclothepin (5) loratadine (9) H N N Cl N N N cinnarizine (3) O N N N H Cl N Cl N N N O O N loxapine (5) N amoxapine (1) oxatomide (9) O O Adrenoceptor (1) Antibiotic (2) Ca2+ Channel (3) Cyclic Nucleotide (4) Dopamine (5) Hormone (6) Phosphorylation (7) Serotonin (8) Other (9) Supplementary Fig. -
Role of Μ, Κ, and Δ Opioid Receptors in Tibial Inhibition of Bladder Overactivity in Cats
JPET Fast Forward. Published on September 9, 2015 as DOI: 10.1124/jpet.115.226845 This article has not been copyedited and formatted. The final version may differ from this version. JPET #226845 Role of µ, κ, and δ Opioid Receptors in Tibial Inhibition of Bladder Overactivity in Cats Zhaocun Zhang, Richard C. Slater, Matthew C. Ferroni, Brian Kadow, Timothy D. Lyon Bing Shen, Zhiying Xiao, Jicheng Wang, Audry Kang James R. Roppolo, William C. de Groat, Changfeng Tai Downloaded from Department of Urology, Qilu Hospital, Shandong University, Jinan, P.R. China (Z.Z.) Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA (Z.Z, R.C.S, M.C.F., B.K., T.D.L., B.S., Z.X., J.W., A.K., C.T.) Department of Urology, The Second Hospital, Shandong University, Jinan, P.R. China (Z.X.) jpet.aspetjournals.org Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA (J.R.R., W.C.D., C.T.) at ASPET Journals on September 25, 2021 Page 1 JPET Fast Forward. Published on September 9, 2015 as DOI: 10.1124/jpet.115.226845 This article has not been copyedited and formatted. The final version may differ from this version. JPET #226845 Running title: Opioid receptors in tibial inhibition of bladder Number of pages: 24 Number of figures: 9 Number of references: 32 Number of words in abstract: 236 Downloaded from Number of words in introduction: 385 Number of words in discussion: 1432 jpet.aspetjournals.org Abbreviations: AA, acetic acid; CMG, cystometrogram; FDA, Food and Drug Administration; OAB, overactive bladder; OR, opioid receptor; PAG, periaqueductal gray; PMC, pontine micturition center; TNS, tibial nerve stimulation; T, threshold Recommended Section: Gastrointestinal, Hepatic, Pulmonary, and Renal at ASPET Journals on September 25, 2021 Corresponding to: Changfeng Tai, Ph.D.