4Th Meeting Program and Abstract Book
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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. -
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. -
Supplementary Materials
Supplementary Materials Hyporesponsivity to mu-opioid receptor agonism in the Wistar-Kyoto rat model of altered nociceptive responding associated with negative affective state Running title: Effects of mu-opioid receptor agonism in Wistar-Kyoto rats Mehnaz I Ferdousi1,3,4, Patricia Calcagno1,2,3,4, Morgane Clarke1,2,3,4, Sonali Aggarwal1,2,3,4, Connie Sanchez5, Karen L Smith5, David J Eyerman5, John P Kelly1,3,4, Michelle Roche2,3,4, David P Finn1,3,4,* 1Pharmacology and Therapeutics, 2Physiology, School of Medicine, 3Centre for Pain Research and 4Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland. 5Alkermes Inc., Waltham, Massachusetts, USA. *Corresponding author: Professor David P Finn, Pharmacology and Therapeutics, School of Medicine, Human Biology Building, National University of Ireland Galway, University Road, Galway, H91 W5P7, Ireland. Tel: +353 (0)91 495280 E-mail: [email protected] S.1. Supplementary methods S.1.1. Elevated plus maze test The elevated plus maze (EPM) test assessed the effects of drug treatment on anxiety-related behaviours in WKY and SD rats. The wooden arena, which was elevated 50 cm above the floor, consisted of central platform (10x10 cm) connecting four arms (50x10 cm each) in the shape of a “plus”. Two arms were enclosed by walls (30 cm high, 25 lux) and the other two arms were without any enclosure (60 lux). On the test day, 5 min after the HPT, rats were removed from the home cage, placed in the centre zone of the maze with their heads facing an open arm, and the behaviours were recorded for 5 min with a video camera positioned on top of the arena. -
52Nd Annual Meeting
ACNP 52nd Annual Meeting Final Program December 8-12, 2013 The Westin Diplomat Resort & Spa Hollywood, Florida President: David A. Lewis, M.D. Program Committee Chair: Randy D. Blakely, Ph.D. Program Committee Co-Chair: Pat R. Levitt, Ph.D. This meeting is jointly sponsored by the Vanderbilt University School of Medicine Department of Psychiatry and the American College of Neuropsychopharmacology. Dear ACNP Members and Guests, It is a distinct pleasure to welcome you to the 2014 meeting of the American College of Neuropsychopharmacology! This 52nd annual meeting will again provide opportunities for the exercise of the College’s core values: the spirit of Collegiality, promoting in each other the best in science, training and service; participation in Community, pursuing together the goals of understanding the neurobiology of brain diseases and eliminating their burden on individuals and our society; and engaging in Celebration, taking the time to recognize and enjoy the contributions and accomplishments of our members and guests. Under the excellent leadership of Randy Blakely and Pat Levitt, the Program Committee has done a superb job in assembling an outstanding slate of scientific presentations. Based on membership feedback, the meeting schedule has been designed with the goals of achieving an optimal mix of topics and types of sessions, increasing the diversity of participating scientists and creating more time for informal interactions. The presentations will highlight both the breadth of the investigative interests of ACNP membership -
(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. -
Behavioral and Brain Sciences Plasticity: Implications for Opioid
Behavioral and Brain Sciences http://journals.cambridge.org/BBS Additional services for Behavioral and Brain Sciences: Email alerts: Click here Subscriptions: Click here Commercial reprints: Click here Terms of use : Click here Plasticity: Implications for opioid and other pharmacological interventions in specific pain states Anthony H. Dickenson Behavioral and Brain Sciences / Volume 20 / Issue 03 / September 1997, pp 392 403 DOI: null, Published online: 08 September 2000 Link to this article: http://journals.cambridge.org/abstract_S0140525X97241488 How to cite this article: Anthony H. Dickenson (1997). Plasticity: Implications for opioid and other pharmacological interventions in specific pain states. Behavioral and Brain Sciences,20, pp 392403 Request Permissions : Click here Downloaded from http://journals.cambridge.org/BBS, IP address: 144.82.107.43 on 10 Aug 2012 BEHAVIORAL AND BRAIN SCIENCES (1997) 20, 392±403 Printed in the United States of America Plasticity: Implications for opioid and other pharmacological interventions in specific pain states Anthony H. Dickenson Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom Electronic mail: anthony.dickenson6ucl.ac.uk Abstract: The spinal mechanisms of action of opioids under normal conditions are reasonably well understood. The spinal effects of opioids can be enhanced or reduced depending on pathology and activity in other segmental and nonsegmental pathways. This plasticity will be considered in relation to the control of different pain states using opioids. The complex and contradictory findings on the supraspinal actions of opioids are explicable in terms of heterogeneous descending pathways to different spinal targets using multiple transmitters and receptors ± therefore opioids can both increase and decrease activity in descending pathways. -
Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands
Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands By Stephanie Nicole Johnson Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Masters in Science. Chairperson: Dr. Thomas E. Prisinzano Dr. Apurba Dutta Dr. Jeffrey P. Krise Date Defended: May 2, 2017 The Thesis Committee for Stephanie Nicole Johnson certifies that this is the approved version of the following thesis: Design and Synthesis of Functionally Selective Kappa Opioid Receptor Ligands Chairperson: Dr. Thomas E. Prisinzano Date approved: May 4, 2017 ii Abstract The ability of ligands to differentially regulate the activity of signaling pathways coupled to a receptor potentially enables researchers to optimize therapeutically relevant efficacies, while minimizing activity at pathways that lead to adverse effects. Recent studies have demonstrated the functional selectivity of kappa opioid receptor (KOR) ligands acting at KOR expressed by rat peripheral pain sensing neurons. In addition, KOR signaling leading to antinociception and dysphoria occur via different pathways. Based on this information, it can be hypothesized that a functionally selective KOR agonist would allow researchers to optimize signaling pathways leading to antinociception while simultaneously minimizing activity towards pathways that result in dysphoria. In this study, our goal was to alter the structure of U50,488 such that efficacy was maintained for signaling pathways important for antinociception (inhibition of cAMP accumulation) and minimized for signaling pathways that reduce antinociception. Thus, several compounds based on the U50,488 scaffold were designed, synthesized, and evaluated at KORs. Selected analogues were further evaluated for inhibition of cAMP accumulation, activation of extracellular signal-regulated kinase (ERK), and inhibition of calcitonin gene- related peptide release (CGRP). -
Cannabinoid Transmission in the Prelimbic Cortex Bidirectionally
15642 • The Journal of Neuroscience, September 25, 2013 • 33(39):15642–15651 Behavioral/Cognitive Cannabinoid Transmission in the Prelimbic Cortex Bidirectionally Controls Opiate Reward and Aversion Signaling through Dissociable Kappa Versus -Opiate Receptor Dependent Mechanisms Tasha Ahmad,1 Nicole M. Lauzon,1 Xavier de Jaeger,1 and Steven R. Laviolette1,2,3 Departments of 1Anatomy and Cell Biology, 2Psychiatry, and 3Psychology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N5Y 5T8 Cannabinoid, dopamine (DA), and opiate receptor pathways play integrative roles in emotional learning, associative memory, and sensory perception. Modulation of cannabinoid CB1 receptor transmission within the medial prefrontal cortex (mPFC) regulates the emotional valence of both rewarding and aversive experiences. Furthermore, CB1 receptor substrates functionally interact with opiate- related motivational processing circuits, particularly in the context of reward-related learning and memory. Considerable evidence demonstrates functional interactions between CB1 and DA signaling pathways during the processing of motivationally salient informa- tion. However, the role of mPFC CB1 receptor transmission in the modulation of behavioral opiate-reward processing is not currently known. Using an unbiased conditioned place preference paradigm with rats, we examined the role of intra-mPFC CB1 transmission during opiate reward learning. We report that activation or inhibition of CB1 transmission within the prelimbic cortical (PLC) division of the mPFC bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission as systemic blockade of DAergic transmission prevented CB1-dependent modulation of morphine reward and aversion behaviors. -
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. -
Biased Signaling by Endogenous Opioid Peptides
Biased signaling by endogenous opioid peptides Ivone Gomesa, Salvador Sierrab,1, Lindsay Lueptowc,1, Achla Guptaa,1, Shawn Goutyd, Elyssa B. Margolise, Brian M. Coxd, and Lakshmi A. Devia,2 aDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029; bDepartment of Physiology & Biophysics, Virginia Commonwealth University, Richmond, VA 23298; cSemel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095; dDepartment of Pharmacology & Molecular Therapeutics, Uniformed Services University, Bethesda MD 20814; and eDepartment of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA 94143 Edited by Susan G. Amara, National Institutes of Health, Bethesda, MD, and approved April 14, 2020 (received for review January 20, 2020) Opioids, such as morphine and fentanyl, are widely used for the possibility that endogenous opioid peptides could vary in this treatment of severe pain; however, prolonged treatment with manner as well (13). these drugs leads to the development of tolerance and can lead to For opioid receptors, studies showed that mice lacking opioid use disorder. The “Opioid Epidemic” has generated a drive β-arrestin2 exhibited enhanced and prolonged morphine-mediated for a deeper understanding of the fundamental signaling mecha- antinociception, and a reduction in side-effects, such as devel- nisms of opioid receptors. It is generally thought that the three opment of tolerance and acute constipation (15, 16). This led to types of opioid receptors (μ, δ, κ) are activated by endogenous studies examining whether μOR agonists exhibit biased signaling peptides derived from three different precursors: Proopiomelano- (17–20), and to the identification of agonists that preferentially cortin, proenkephalin, and prodynorphin. -
Structure of the Human Κ-Opioid Receptor in Complex with Jdtic
ARTICLE doi:10.1038/nature10939 Structure of the human k-opioid receptor in complex with JDTic Huixian Wu1, Daniel Wacker1, Mauro Mileni1, Vsevolod Katritch1, Gye Won Han1, Eyal Vardy2, Wei Liu1, Aaron A. Thompson1, Xi-Ping Huang2, F. Ivy Carroll3, S. Wayne Mascarella3, Richard B. Westkaemper4, Philip D. Mosier4, Bryan L. Roth2, Vadim Cherezov1 & Raymond C. Stevens1 Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and—in the case of k-opioid receptor (k-OR)—dysphoria and psychotomimesis. Here we report the crystal structure of the human k-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 A˚ resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human k-OR. Modelling of other important k-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 59-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure–activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for k-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human k-OR. The four opioid receptors, m, d, k and the nociceptin/orphanin FQ antidepressants, anxiolytics and anti-addiction medications14, whereas peptide receptor, belong to the class A (rhodopsin-like) c subfamily of a widely abused, naturally occurring hallucinogen—salvinorin A G-protein-coupled receptors (GPCRs)1 with a common seven- (SalA)—was also found to be a highly selective k-OR agonist15.