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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. -
Current Awareness in Clinical Toxicology Editors: Damian Ballam Msc and Allister Vale MD
Current Awareness in Clinical Toxicology Editors: Damian Ballam MSc and Allister Vale MD February 2016 CONTENTS General Toxicology 9 Metals 38 Management 21 Pesticides 41 Drugs 23 Chemical Warfare 42 Chemical Incidents & 32 Plants 43 Pollution Chemicals 33 Animals 43 CURRENT AWARENESS PAPERS OF THE MONTH How toxic is ibogaine? Litjens RPW, Brunt TM. Clin Toxicol 2016; online early: doi: 10.3109/15563650.2016.1138226: Context Ibogaine is a psychoactive indole alkaloid found in the African rainforest shrub Tabernanthe Iboga. It is unlicensed but used in the treatment of drug and alcohol addiction. However, reports of ibogaine's toxicity are cause for concern. Objectives To review ibogaine's pharmacokinetics and pharmacodynamics, mechanisms of action and reported toxicity. Methods A search of the literature available on PubMed was done, using the keywords "ibogaine" and "noribogaine". The search criteria were "mechanism of action", "pharmacokinetics", "pharmacodynamics", "neurotransmitters", "toxicology", "toxicity", "cardiac", "neurotoxic", "human data", "animal data", "addiction", "anti-addictive", "withdrawal", "death" and "fatalities". The searches identified 382 unique references, of which 156 involved human data. Further research revealed 14 detailed toxicological case reports. Current Awareness in Clinical Toxicology is produced monthly for the American Academy of Clinical Toxicology by the Birmingham Unit of the UK National Poisons Information Service, with contributions from the Cardiff, Edinburgh, and Newcastle Units. The NPIS is commissioned by Public Health England Current Awareness in Clinical Toxicology Editors: Damian Ballam MSc and Allister Vale MD February 2016 Current Awareness in Clinical Toxicology is produced monthly for the American Academy of Clinical Toxicology by the Birmingham Unit of the UK National Poisons Information Service, with contributions from the Cardiff, Edinburgh, and Newcastle Units. -
Euphoric Non-Fentanil Novel Synthetic Opioids on the Illicit Drugs Market
Forensic Toxicology (2019) 37:1–16 https://doi.org/10.1007/s11419-018-0454-5 REVIEW ARTICLE The search for the “next” euphoric non‑fentanil novel synthetic opioids on the illicit drugs market: current status and horizon scanning Kirti Kumari Sharma1,2 · Tim G. Hales3 · Vaidya Jayathirtha Rao1,2 · Niamh NicDaeid4,5 · Craig McKenzie4 Received: 7 August 2018 / Accepted: 11 November 2018 / Published online: 28 November 2018 © The Author(s) 2018 Abstract Purpose A detailed review on the chemistry and pharmacology of non-fentanil novel synthetic opioid receptor agonists, particularly N-substituted benzamides and acetamides (known colloquially as U-drugs) and 4-aminocyclohexanols, developed at the Upjohn Company in the 1970s and 1980s is presented. Method Peer-reviewed literature, patents, professional literature, data from international early warning systems and drug user fora discussion threads have been used to track their emergence as substances of abuse. Results In terms of impact on drug markets, prevalence and harm, the most signifcant compound of this class to date has been U-47700 (trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide), reported by users to give short- lasting euphoric efects and a desire to re-dose. Since U-47700 was internationally controlled in 2017, a range of related compounds with similar chemical structures, adapted from the original patented compounds, have appeared on the illicit drugs market. Interest in a structurally unrelated opioid developed by the Upjohn Company and now known as BDPC/bromadol appears to be increasing and should be closely monitored. Conclusions International early warning systems are an essential part of tracking emerging psychoactive substances and allow responsive action to be taken to facilitate the gathering of relevant data for detailed risk assessments. -
(19) United States (12) Patent Application Publication (10) Pub
US 20100227876A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0227876 A1 Rech (43) Pub. Date: Sep. 9, 2010 (54) METHODS OF REDUCING SIDE EFFECTS Publication Classi?cation OF ANALGESICS (51) Int CL A61K 31/485 (2006.01) A61K 31/40 (2006.01) (75) Inventor: Richard H. Rech, Okemos, MI A61K 31/445 (2006-01) (Us) A61K 31/439 (2006.01) (52) US. Cl. ........................ .. 514/282; 514/409; 514/329 (57) ABSTRACT Correspondence Address: The invention provides for compositions and methods of MARSHALL, GERSTEIN & BORUN LLP reducing pain in a subject by administering a combination of 233 SOUTH WACKER DRIVE, 6300 WILLIS mu-opioid receptor agonist, kappal-opioid receptor agonist TOWER and a nonselective opioid receptor antagonist in amounts CHICAGO, IL 60606-6357 (US) effective to reduce pain and ameliorate an adverse side effect of treatment combining opioid-receptor agonists. The inven tion also provides for methods of enhancing an analgesic effect of treatment With an opioid-receptor agonist in a sub (73) Assignee: RECHFENSEN LLP, RidgeWood, ject suffering from pain While reducing an adverse side effect NJ (US) of the treatment. The invention also provides for methods of reducing the hyperalgesic effect of treatment With an opioid receptor agonist in a subject suffering from pain While reduc ing an adverse side effect of the treatment. The invention (21) Appl. No.: 12/399,629 further provides for methods of promoting the additive anal gesia of pain treatment With an opioid-receptor agonist in a subject in need While reducing an adverse side effect of the (22) Filed: Mar. -
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. -
Table of Contents
TheJournalof VOLUME271 PHARMACOLOGY NUMBER 3 AND EXPERIMENTAL THERAPEUTICS Contents ANTI-INFLAMMATORIES Lecithinized Superoxide Dismutase Enhances Its R. Igarashi, J. Hoshino, A. Ochiai, 1672 Pharmacologic Potency by Increasing Its Cell Membrane Y. Morizawa and Y. Mizushima Affinity ANALGESICS Role of Endogenous Cholecystokinin in the Facilitation of Mu- Florence Noble, Claire Smadja and 1127 Mediated Antinociception by Delta.Opioid Agonists Bernard P. Roques Downloaded from GBR12909 Attenuates Cocaine-Induced Activation of Michael H. Baumann, George U. Char, 1216 Mesolimbic Dopamine Neurons in the Rat Brian R. Dc Costa, Kenner C. Rice and Richard B. Rothman Substance P N-Terminal Metabolites and Nitric Oxide Mediate Julie S. Kreeger, Kelley F. Kitto and 1281 Capsaicin-Induced Antinociception in the Adult Mouse Alice A. Larson Antinociceptive Actions of Dexmedetomidine and the Kappa- Juhana J. Idanpaan-Heikkila, Eija A. Kalso 1306 jpet.aspetjournals.org Opioid Agonist U.5O,488H against Noxious Thermal, and Timo Seppala Mechanical and Inflammatory Stimuli Involvement of NMDA Receptors in Naloxone-Induced Rustam Yu. Yukhananov and 1365 Contractions of the Isolated Guinea Pig ileum after Alice A. Larson Preincubation with Morphine Development of Cross-Tolerance between - Fang Fan, David R. Compton, Susan Ward, 1383 Tetrahydrocannabinol, CP 55,940 and WIN 55,212 Lawrence Melvin and Billy R. Martin at ASPET Journals on October 2, 2021 Antinociceptive and Response Rate-Altering Effects of Kappa Raymond C. Pitts and Linda A. Dykstra 1501 Opioid Agonists, Spiradoline, Enadoline and U69,593, Alone and in Combination with Opioid Antagonists in Squirrel Monkeys The Influence of Pharmacogenetics on Opioid Analgesia: Jim Cleary, Gerd Mikus, Andrew Somogyi 1528 Studies with Codeine and Oxycodone in the Sprague-Dawley/ and Felix Bochner Dark Agouti Rat Model Selective Antagonism of Opioid Analgesia by a Sigma System Chih-Cheng Chien and 1583 Gavril W. -
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. -
In the IUPHAR/BPS Guide to Pharmacology Database
IUPHAR/BPS Guide to Pharmacology CITE https://doi.org/10.2218/gtopdb/F16/2019.4 Class A Orphans (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database Stephen P.H. Alexander1, Jim Battey2, Helen E. Benson3, Richard V. Benya4, Tom I. Bonner5, Anthony P. Davenport6, Satoru Eguchi7, Anthony Harmar3, Nick Holliday1, Robert T. Jensen2, Sadashiva Karnik8, Evi Kostenis9, Wen Chiy Liew3, Amy E. Monaghan3, Chido Mpamhanga10, Richard Neubig11, Adam J. Pawson3, Jean-Philippe Pin12, Joanna L. Sharman3, Michael Spedding13, Eliot Spindel14, Leigh Stoddart15, Laura Storjohann16, Walter G. Thomas17, Kalyan Tirupula8 and Patrick Vanderheyden18 1. University of Nottingham, UK 2. National Institutes of Health, USA 3. University of Edinburgh, UK 4. University of Illinois at Chicago, USA 5. National Institute of Mental Health, USA 6. University of Cambridge, UK 7. Temple University, USA 8. Cleveland Clinic Lerner Research Institute, USA 9. University of Bonn, Germany 10. LifeArc, UK 11. Michigan State University, USA 12. Université de Montpellier, France 13. Spedding Research Solutions SARL, France 14. Oregon Health & Science University, USA 15. University of Glasgow, UK 16. University of Utah, USA 17. University of Queensland, Australia 18. Vrije Universiteit Brussel, Belgium Abstract Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [191], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [148]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands. -
Differential Regulation of Serotonin 2A Receptor Responsiveness by Agonist
Differential regulation of serotonin 2A receptor responsiveness by agonist- directed interactions with arrestin2 DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Cullen Laura Schmid, B.S. Neuroscience Graduate Studies Program The Ohio State University 2011 Dissertation Committee: Laura M. Bohn, Co-advisor Georgia A. Bishop, Co-advisor Candice C. Askwith Wolfgang Sadee Copyright by Cullen Laura Schmid 2011 Abstract The G protein-coupled, serotonin 2A (5-HT2A) receptor is a major drug target for the treatment of a number of mental health disorders, including schizophrenia, anxiety and depression. In addition to modulating several of the physiological effects of the neurotransmitter serotonin, activation of the 5-HT2A receptor mediates the psychotomimetic effects of serotonergic hallucinogenic drugs, such as lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine (DOI) and 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT). Though hallucinogens are agonists at the 5-HT2A receptor, not all 5-HT2A receptor agonists induce hallucinations in humans, including the endogenous ligand serotonin. Therefore, the activation of the 5-HT2A receptor can result in different biological responses depending upon the chemical nature of the ligand, a concept that has been referred to as “functional selectivity.” One way in which ligands can induce differential signaling at GPCRs is through interactions with arrestins, which can act to dampen or facilitate receptor signaling cascades or mediate the internalization of receptors into intracellular vesicles. The overarching hypothesis of this dissertation is that the interaction between the regulatory protein, arrestin2, and the 5-HT2A receptor is a critical point in the divergence of agonist-directed 5-HT2A receptor responsiveness. -
Bias-Inducing Allosteric Binding Site in Mu-Opioid Receptor Signaling
Research Article Bias‑inducing allosteric binding site in mu‑opioid receptor signaling Andrés F. Marmolejo‑Valencia1 · Abraham Madariaga‑Mazón1 · Karina Martinez‑Mayorga1 Received: 23 January 2021 / Accepted: 12 March 2021 © The Author(s) 2021 OPEN Abstract G-protein-biased agonism of the mu-opioid receptor (μ-OR) is emerging as a promising strategy in analgesia. A deep understanding of how biased agonists modulate and diferentiate G-protein-coupled receptors (GPCR) signaling path- ways and how this is transferred into the cell are open questions. Here, using extensive all-atom molecular dynamics simulations, we analyzed the binding recognition process and signaling efects of three prototype μ-OR agonists. Our suggested structural mechanism of biased signaling in μ-OR involves an allosteric sodium ion site, water networks, confor- mational rearrangements in conserved motifs and collective motions of loops and transmembrane helices. These analyses led us to highlight the relevance of a bias-inducing allosteric binding site in the understanding of μ-OR’s G-protein-biased signaling. These results also suggest a competitive equilibrium between the agonists and the allosteric sodium ion, where the bias-inducing allosteric binding site can be modulated by this ion or an agonist such as herkinorin. Notably, herkinorin arises as the archetype modulator of μ-OR and its interactive pattern could be used for screening eforts via protein–ligand interaction fngerprint (PLIF) studies. Article highlights • Agonists and a sodium ion compete for the bias-inducing allosteric binding site that modulates signaling in mu-opioid receptors. • Molecular dynamics simulations of the prototype μ-OR agonist suggest a competitive equilibrium involving the agonist and an allosteric sodium ion. -
Fiona Bull Thesis Final Dec15.Pdf
University of Dundee DOCTOR OF PHILOSOPHY Targeting Opioid Receptor Signal Transduction to Produce Sustained Analgesia Bull, Fiona A. Award date: 2015 Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 04. Oct. 2021 Targeting Opioid Receptor Signal Transduction to Produce Sustained Analgesia Fiona A Bull BSc(Hons), MBChB, FRCA Thesis submitted in candidature for the degree of Doctor of Philosophy, University of Dundee, November 2015. i Table of Contents List of Tables -------------------------------------------------------------------------------------- vi List of Figures ------------------------------------------------------------------------------------ vii Abbreviations ----------------------------------------------------------------------------------- xii Acknowledgements -
212102Orig1s000
CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 212102Orig1s000 OTHER REVIEW(S) Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research | Office of Surveillance and Epidemiology (OSE) Epidemiology: ARIA Sufficiency Date: June 29, 2020 Reviewer: Silvia Perez-Vilar, PharmD, PhD Division of Epidemiology I Team Leader: Kira Leishear, PhD, MS Division of Epidemiology I Division Director: CAPT Sukhminder K. Sandhu, PhD, MPH, MS Division of Epidemiology I Subject: ARIA Sufficiency Memo for Fenfluramine-associated Valvular Heart Disease and Pulmonary Arterial Hypertension Drug Name(s): FINTEPLA (Fenfluramine hydrochloride, ZX008) Application Type/Number: NDA 212102 Submission Number: 212102/01 Applicant/sponsor: Zogenix, Inc. OSE RCM #: 2020-953 The original ARIA memo was dated June 23, 2020. This version, dated June 29, 2020, was amended to include “Assess a known serious risk” as FDAAA purpose (per Section 505(o)(3)(B)) to make it consistent with the approved labeling. The PMR development template refers to the original memo, dated June 23, 2020. Page 1 of 13 Reference ID: 46331494640015 EXECUTIVE SUMMARY (place “X” in appropriate boxes) Memo type -Initial -Interim -Final X X Source of safety concern -Peri-approval X X -Post-approval Is ARIA sufficient to help characterize the safety concern? Safety outcome Valvular Pulmonary heart arterial disease hypertension (VHD) (PAH) -Yes -No X X If “No”, please identify the area(s) of concern. -Surveillance or Study Population X X -Exposure -Outcome(s) of Interest X X -Covariate(s) of Interest X X -Surveillance Design/Analytic Tools Page 2 of 13 Reference ID: 46331494640015 1.