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APHAR 2012 Abstract Preview MEETING ABSTRACTS 18th Scientific Symposium of the Austrian Pharmacological Society (APHAR) Joint Meeting with the Croatian, Serbian and Slovenian Pharmacological Societies Graz, Austria, 20–21 September 2012 A1 Acknowledgements: This work was supported in part by the Antidepressant-like effects of benzodiazepine site inverse Ministry of Education and Science, Republic of Serbia, grant no. agonists in the rat forced swim test 175076. Janko Samardžić and Dragan I Obradović Institute of Pharmacology, Clinical Pharmacology and Toxicology, A2 Medical Faculty, University of Belgrade, 11129 Belgrade, Serbia Methadone-drugs interactions: possible causes of methadone- E-mail: [email protected] related deaths Vesna Mijatović1, Isidora Samojlik1, Stojan Petković2 and Nikša Background: There are three kinds of allosteric modulators acting 2 Ajduković through the benzodiazepine (BZ) binding site of the GABA 1 A Department of Pharmacology, Toxicology and Clinical receptor: positive (agonist), neutral (antagonist), and negative Pharmacology, Faculty of Medicine, University of Novi Sad, 21000 (inverse agonist) modulators. Agonists and inverse agonists 2 Novi Sad, Serbia; Department of Forensic Medicine, Faculty of commonly exert bidirectional influences on observed behavioral Medicine, University of Novi Sad, 21000 Novi Sad, Serbia parameters. In the present study we have investigated the E-mail: [email protected] modulation of behavioral responses to environmental novelty in two unconditioned paradigms: spontaneous locomotor activity (SLA) and Background: Methadone is an effective analgesic and it is widely forced swim test (FST), elicited by DMCM (methyl-6,7-dimethoxy-4- used to suppress withdrawal symptoms from other opiates. Its ethyl-beta-carboline-3-carboxylate), a non-selective inverse agonist, consumption is usually associated with concomitant drug use in in the dose range that previously did not produce anxiogenic effects heroin addicts, and this combination is a possible risk factor for and convulsions. -
Ong Edmund W 201703 Phd.Pdf (5.844Mb)
INVESTIGATING THE EFFECTS OF PROLONGED MU OPIOID RECEPTOR ACTIVATION UPON OPIOID RECEPTOR HETEROMERIZATION by Edmund Wing Ong A thesis submitted to the Graduate Program in Pharmacology & Toxicology in the Department of Biomedical and Molecular Sciences In conformity with the requirements for the degree of Doctor of Philosophy Queen’s University Kingston, Ontario, Canada March, 2017 Copyright © Edmund Wing Ong, 2017 Abstract Opioid receptors are the sites of action for morphine and most other clinically-used opioid drugs. Abundant evidence now demonstrates that different opioid receptor types can physically associate to form heteromers. Owing to their constituent monomers’ involvement in analgesia, mu/delta opioid receptor (M/DOR) heteromers have been a particular focus of attention. Understandings of the physiological relevance of M/DOR formation remain limited in large part due to the reliance of existing M/DOR findings upon contrived heterologous systems. This thesis investigated the physiological relevance of M/DOR generation following prolonged MOR activation. To address M/DOR in endogenous tissues, suitable model systems and experimental tools were established. This included a viable dorsal root ganglion (DRG) neuron primary culture model, antisera specifically directed against M/DOR, a quantitative immunofluorescence colocalizational analysis method, and a floxed-Stop, FLAG-tagged DOR conditional knock-in mouse model. The development and implementation of such techniques make it possible to conduct experiments addressing the nature of M/DOR heteromers in systems with compelling physiological relevance. Seeking to both reinforce and extend existing findings from heterologous systems, it was first necessary to demonstrate the existence of M/DOR heteromers. Using antibodies directed against M/DOR itself as well as constituent monomers, M/DOR heteromers were identified in endogenous tissues and demonstrated to increase in abundance following prolonged mu opioid receptor (MOR) activation by morphine. -
Example of a Scientific Poster
Janet Robishaw, PhD Senior Associate Dean for Research Chair and Professor, Biomedical Science Florida Atlantic University Charles E. Schmidt College of Medicine Disclosures and Conflicts • I have no actual or potential conflict of interest in relation to this program/presentation. • Research support: Robishaw, MPI Robishaw, MPI R01 DA044015 R01 HL134015 Genetic Predictors of Opioid Addiction Genetic Heterogeneity of Sleep Apnea 2017-2022 2016-2021 Robishaw, PI Robishaw, MPI R01 GM114665 R01 GM111913 Novel Aspects of Golf Signaling GPCR Variants in Complex Diseases 2015-2019 2015-2019 Learning Objectives 1. Review the scope and root cause of opioid use disorder 2. Discuss the effects of opioid medications on the brain and body 3. Stress the importance of clinical judgement and discovery to address the opioid crisis 4. Highlight the clinical implications between opioid use disorder and heroin abuse Two Endemic Problems Chronic Pain Opioid Use Disorder Debilitating disorder Chronic, relapsing disorder 100 million Americans 2 million Americans Costs $630 billion dollars per year Costs $80 billion per year #1 presenting complaint to doctors # 1 cause of accidental death #1 reason for lost productivity #1 driver of heroin epidemic #1 treatment –opioid medications ? treatment Pain Relief and “Addiction” Share A Common Mechanism of Action m-Opioid Receptor Brain Regions Involved in Pleasure and Reward Increase dopamine release Brain Regions Involved in Pain Perception Brainstem Involved in Respiratory Control Spinal Cord Involved in Pain Transmission Prevent ascending transmission Turn on descending inhibitory systems These receptors are dispersed Inhibit peripheral nocioceptors throughout the body, thereby accounting for their differential Body effects on pain and reward paths. -
Biased Versus Partial Agonism in the Search for Safer Opioid Analgesics
molecules Review Biased versus Partial Agonism in the Search for Safer Opioid Analgesics Joaquim Azevedo Neto 1 , Anna Costanzini 2 , Roberto De Giorgio 2 , David G. Lambert 3 , Chiara Ruzza 1,4,* and Girolamo Calò 1 1 Department of Biomedical and Specialty Surgical Sciences, Section of Pharmacology, University of Ferrara, 44121 Ferrara, Italy; [email protected] (J.A.N.); [email protected] (G.C.) 2 Department of Morphology, Surgery, Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy; [email protected] (A.C.); [email protected] (R.D.G.) 3 Department of Cardiovascular Sciences, Anesthesia, Critical Care and Pain Management, University of Leicester, Leicester LE1 7RH, UK; [email protected] 4 Technopole of Ferrara, LTTA Laboratory for Advanced Therapies, 44122 Ferrara, Italy * Correspondence: [email protected] Academic Editor: Helmut Schmidhammer Received: 23 July 2020; Accepted: 23 August 2020; Published: 25 August 2020 Abstract: Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2( / )) animals indicate that morphine analgesia is potentiated − − while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2( / ) mice. Moreover, − − studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. -
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. -
Summary Analgesics Dec2019
Status as of December 31, 2019 UPDATE STATUS: N = New, A = Advanced, C = Changed, S = Same (No Change), D = Discontinued Update Emerging treatments for acute and chronic pain Development Status, Route, Contact information Status Agent Description / Mechanism of Opioid Function / Target Indication / Other Comments Sponsor / Originator Status Route URL Action (Y/No) 2019 UPDATES / CONTINUING PRODUCTS FROM 2018 Small molecule, inhibition of 1% diacerein TWi Biotechnology / caspase-1, block activation of 1 (AC-203 / caspase-1 inhibitor Inherited Epidermolysis Bullosa Castle Creek Phase 2 No Topical www.twibiotech.com NLRP3 inflamasomes; reduced CCP-020) Pharmaceuticals IL-1beta and IL-18 Small molecule; topical NSAID Frontier 2 AB001 NSAID formulation (nondisclosed active Chronic low back pain Phase 2 No Topical www.frontierbiotech.com/en/products/1.html Biotechnologies ingredient) Small molecule; oral uricosuric / anti-inflammatory agent + febuxostat (xanthine oxidase Gout in patients taking urate- Uricosuric + 3 AC-201 CR inhibitor); inhibition of NLRP3 lowering therapy; Gout; TWi Biotechnology Phase 2 No Oral www.twibiotech.com/rAndD_11 xanthine oxidase inflammasome assembly, reduced Epidermolysis Bullosa Simplex (EBS) production of caspase-1 and cytokine IL-1Beta www.arraybiopharma.com/our-science/our-pipeline AK-1830 Small molecule; tropomyosin Array BioPharma / 4 TrkA Pain, inflammation Phase 1 No Oral www.asahi- A (ARRY-954) receptor kinase A (TrkA) inhibitor Asahi Kasei Pharma kasei.co.jp/asahi/en/news/2016/e160401_2.html www.neurosmedical.com/clinical-research; -
Pain Therapy E Are There New Options on the Horizon?
Best Practice & Research Clinical Rheumatology 33 (2019) 101420 Contents lists available at ScienceDirect Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh 4 Pain therapy e Are there new options on the horizon? * Christoph Stein a, , Andreas Kopf b a Department of Experimental Anesthesiology, Charite Campus Benjamin Franklin, D-12200 Berlin, Germany b Department of Anesthesiology and Intensive Care Medicine, Charite Campus Benjamin Franklin, D-12200 Berlin, Germany abstract Keywords: Opioid crisis This article reviews the role of analgesic drugs with a particular Chronic noncancer pain emphasis on opioids. Opioids are the oldest and most potent drugs Chronic nonmalignant pain for the treatment of severe pain, but they are burdened by detri- Opioid mental side effects such as respiratory depression, addiction, Opiate sedation, nausea, and constipation. Their clinical application is Inflammation undisputed in acute (e.g., perioperative) and cancer pain, but their Opioid receptor long-term use in chronic pain has met increasing scrutiny and has Misuse Abuse contributed to the current opioid crisis. We discuss epidemiolog- Bio-psycho-social ical data, pharmacological principles, clinical applications, and research strategies aiming at novel opioids with reduced side effects. © 2019 Elsevier Ltd. All rights reserved. The opioid epidemic The treatment of pain remains a huge challenge in clinical medicine and public health [1,2]. Pain is the major symptom in rheumatoid (RA) and osteoarthritis (OA) [3,4]. Both are chronic conditions that are not linked to malignant disease, and pain can occur even in the absence of inflammatory signs (see chapter “Pain without inflammation”). Unfortunately, there is a lack of fundamental knowledge about the management of chronic noncancer pain. -
Developments in Opioid Drugs
Spotlight on drugs Developments in opioid Advanced courses 2019 analgesics Dr Andrew Wilcock DM FRCP [email protected] 1 2 1 2 Outline of talk • background – cancer pain / strong opioids Background • pharmacology • new approaches (as we go) • summary • discussion/questions. 3 4 Opioids WHO analgesic ladder for cancer pain • central to the management of moderate–severe acute pain and cancer pain. 5 6 1 Broad-spectrum analgesia Opioids: why improve? Ultimate aim to: • improve efficacy • eliminate / reduce risk of undesirable effects, e.g.: – constipation – dependence – respiratory depression – sedation – tolerance. 7 8 Opioids: chemical classification Pharmacology 9 10 Opioid: receptors Four main types: • μ • κ • δ • opioid-receptor-like 1 (OPRL-1) – opioid-related nociceptin receptor 1 – nociceptin opioid peptide (NOP) – nociceptin/orphanin FQ (N/OFQ). 11 12 2 Opioid: receptors Opioids Generally: • μ-opioid receptor clinically most relevant for analgesia and undesirable effects • Centrally: dorsal horn, higher centres – pre-synaptic: inhibit release of neurotransmitters – post-synaptic: hyperpolarize neurone • Peripherally: nerve endings, DRG, (immune cells) – inflammation upregulates opioid receptors 13 14 15 16 New approaches for opioid analgesics 17 18 3 New approaches for opioid analgesics Include: 1. Broad-spectrum 2. Injury-targeted 1. ‘Broad-spectrum’ opioid agonists 3. Biased agonists Not exhaustive list, but main finds when searching the literature. Gunther T et al. (2018); Chan HCS et al. (2017) 19 20 ‘Broad-spectrum’ opioid agonists Differential analgesic and UE of opioid receptors Targeting multiple receptors may have synergistic analgesic effects & lower UE • μ most important analgesia / UE • selective κ and δ agonists – limited analgesia / own UE – κ (e.g. -
Measuring Ligand Efficacy at the Mu- Opioid Receptor Using A
RESEARCH ARTICLE Measuring ligand efficacy at the mu- opioid receptor using a conformational biosensor Kathryn E Livingston1,2, Jacob P Mahoney1,2, Aashish Manglik3, Roger K Sunahara4, John R Traynor1,2* 1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States; 2Edward F Domino Research Center, University of Michigan, Ann Arbor, United States; 3Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, United States; 4Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, United States Abstract The intrinsic efficacy of orthosteric ligands acting at G-protein-coupled receptors (GPCRs) reflects their ability to stabilize active receptor states (R*) and is a major determinant of their physiological effects. Here, we present a direct way to quantify the efficacy of ligands by measuring the binding of a R*-specific biosensor to purified receptor employing interferometry. As an example, we use the mu-opioid receptor (m-OR), a prototypic class A GPCR, and its active state sensor, nanobody-39 (Nb39). We demonstrate that ligands vary in their ability to recruit Nb39 to m- OR and describe methadone, loperamide, and PZM21 as ligands that support unique R* conformation(s) of m-OR. We further show that positive allosteric modulators of m-OR promote formation of R* in addition to enhancing promotion by orthosteric agonists. Finally, we demonstrate that the technique can be utilized with heterotrimeric G protein. The method is cell- free, signal transduction-independent and is generally applicable to GPCRs. DOI: https://doi.org/10.7554/eLife.32499.001 *For correspondence: [email protected] Competing interests: The authors declare that no Introduction competing interests exist. -
The Main Tea Eta a El Mattitauli Mali Malta
THE MAIN TEA ETA USA 20180169172A1EL MATTITAULI MALI MALTA ( 19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 /0169172 A1 Kariman (43 ) Pub . Date : Jun . 21 , 2018 ( 54 ) COMPOUND AND METHOD FOR A61K 31/ 437 ( 2006 .01 ) REDUCING APPETITE , FATIGUE AND PAIN A61K 9 / 48 (2006 .01 ) (52 ) U . S . CI. (71 ) Applicant : Alexander Kariman , Rockville , MD CPC . .. .. .. .. A61K 36 / 74 (2013 .01 ) ; A61K 9 / 4825 (US ) (2013 . 01 ) ; A61K 31/ 437 ( 2013 . 01 ) ; A61K ( 72 ) Inventor: Alexander Kariman , Rockville , MD 31/ 4375 (2013 .01 ) (US ) ( 57 ) ABSTRACT The disclosed invention generally relates to pharmaceutical (21 ) Appl . No. : 15 /898 , 232 and nutraceutical compounds and methods for reducing appetite , muscle fatigue and spasticity , enhancing athletic ( 22 ) Filed : Feb . 16 , 2018 performance , and treating pain associated with cancer, trauma , medical procedure , and neurological diseases and Publication Classification disorders in subjects in need thereof. The disclosed inven ( 51 ) Int. Ci. tion further relates to Kratom compounds where said com A61K 36 / 74 ( 2006 .01 ) pound contains at least some pharmacologically inactive A61K 31/ 4375 ( 2006 .01 ) component. pronuPatent Applicationolan Publication manu saJun . decor21, 2018 deSheet les 1 of 5 US 2018 /0169172 A1 reta Mitragynine 7 -OM - nitragynine *** * *momoda W . 00 . Paynantheine Speciogynine **** * * * ! 1000 co Speclociliatine Corynartheidine Figure 1 Patent Application Publication Jun . 21, 2018 Sheet 2 of 5 US 2018 /0169172 A1 -
The Utilization of Mu-Opioid Receptor Biased Agonists: Oliceridine, an Opioid Analgesic with Reduced Adverse Effects
Current Pain and Headache Reports (2019) 23: 31 https://doi.org/10.1007/s11916-019-0773-1 HOT TOPICS IN PAIN AND HEADACHE (N. ROSEN, SECTION EDITOR) The Utilization of Mu-Opioid Receptor Biased Agonists: Oliceridine, an Opioid Analgesic with Reduced Adverse Effects Ivan Urits1 & Omar Viswanath2,3,4 & Vwaire Orhurhu1 & Kyle Gress5 & Karina Charipova5 & Alan D. Kaye6 & Anh Ngo1 Published online: 18 March 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review The purpose of this review is to summarize the current understanding of opioid pathways in mediating and/or modulating analgesia and adverse effects. Oliceridine is highlighted as a novel mu-opioid receptor agonist with selective activation of G protein and β-arrestin signaling pathways. Recent Findings Oliceridine (TRV130; [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine) is a novel MOR agonist that selectively activates G protein and β-arrestin signaling pathways. A growing body of evidence suggests that compared to existing MOR agonists, Oliceridine and other G protein-selective modulators may produce therapeutic analgesic effects with reduced adverse effects. Summary Oliceridine provides analgesic benefits of a pure opioid agonist while limiting related adverse effects mediated through the β-arrestin pathway. Recent insights into the function and structure of G protein-coupled receptors has led to the development of novel analgesic therapies. Keywords Oliceridine . TRV130 . G protein-coupled receptors (GPCR) . Partial opioid agonists Introduction significant driver in an effort to develop novel opioid pharma- cotherapies with less adverse side effects. -
Phosphoproteomics Illuminates Opioid Actions Tao Che and Bryan L
Phosphoproteomics Illuminates Opioid Actions Tao Che and Bryan L. Roth* Department of Pharmacology, University of North Carolina School of Medical, Chapel Hill, North Carolina 27514, United States ABSTRACT: Opioids are widely used analgesic medications with a high potential for tolerance and dependence and represent a frequent cause of death due to overdose. Opioids mediate their actions via a family of opioid G protein coupled receptors. Elucidating the biochemical mechanism(s) responsible for both the therapeutic and deleterious side effects of opioids could provide a biochemical roadmap for selectively targeting therapeutic signaling pathways. Here we provide a perspective on emerging findings, which illuminate these signaling pathways via unbiased and quantitative phosphoproteomic analysis. What emerged from these studies is the discovery that certain deleterious actions mediated by the κ opioid receptors appear due to specific activation of mTOR pathways. The findings imply that designing drugs, which bypass mTOR signaling, could yield safer and more effective analgesics. pioid drugs like morphine and oxycodone are powerful with the use of dynorphin- and KOR-knockout mice, they O painkillers that produce analgesia by activation of opioid identified the phosphorylation sites uniquely related to KOR G-protein coupled receptors (GPCRs). Although opioids are activation. The authors determined that the dynamic changes quite useful for alleviating pain, they can also elicit an array of in KOR phosphorylation displayed spatio-temporal control. harmful side effects, such as aversion, hallucinations, addiction, Further analysis of KOR-mediated phosphorylation identified and death by respiratory depression. Thus, a new class of those patterns relevant to specific neuronal circuits, in nonopioid analgesics could go a long way toward alleviating particular, dopamine-, glutamate-, and γ-aminobutyric acid the prevailing opioid crisis.