DOCSLIB.ORG

Breaking Barriers to Novel Analgesic Drug Development

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Breaking Barriers to Novel Analgesic Drug Development REVIEWS Breaking barriers to novel analgesic drug development Ajay S. Yekkirala1–3, David P. Roberson1–3, Bruce P. Bean1 and Clifford J. Woolf1,2 Abstract | Acute and chronic pain complaints, although common, are generally poorly served by existing therapies. This unmet clinical need reflects a failure to develop novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms, and the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors. Pain is the primary reason why people seek medical blockbuster model of one treatment for all pain condi- Analgesics 12 Pharmacological agents or care: more than 40% of the US population is affected tions is not tenable . The poor predictability of preclin- 1 ligands that produce analgesia. by chronic pain . In the United States alone in 2013, the ical ‘pain’ models can result in candidates being selected overall cost of treating certain chronic pain conditions that do not have activity in the conditions suffered by Tolerance amounted to more than US$130 billion2. Currently avail- patients13 (BOX 1). Conversely, difficulty in ensuring A state in which the drug no analgesics longer produces the same able — nonsteroidal anti-inflammatory drugs target engagement, lack of sensitivity of clinical trials effect and a higher dose is (NSAIDs), amine reuptake inhibitors, anti epileptic and distortions induced by placebos increase the risk therefore needed. drugs and opioids — have varying but typically low that potentially effective compounds or targets may levels of analgesic efficacy, which is generally coupled be prematurely abandoned14,15. These issues have led Dependence with deleterious effects2. Indeed, opioids, which are the to most drug developmental efforts being devoted to An adaptive state that develops when a pharmacological agent most commonly used (with ~240 million prescriptions reformulations of existing validated analgesic classes — 3 is used repeatedly and leads to in 2014 in the United States) and often the most effec- opioids, NSAIDs, antiepileptic agents and amine reuptake withdrawal on cessation of the tive class of analgesics, produce tolerance, dependence inhibitors — despite their well-known limitations16. drug regimen. and constipation, and are associated with major abuse Given the prevalence of opioid diversion and over- 1Department of liabilities. Furthermore, the respiratory depression asso- dose, there is an urgent need to develop effective and Neurobiology, Harvard ciated with high doses has led to a catastrophic increase safe analgesics without a liability for abuse. Work from a Medical School, Boston in the number of drug overdose deaths in the United large number of laboratories has shed light on the mech- Children’s Hospital, 300 States3 (see the US Centers for Disease Control and anisms and pathways that mediate specific aspects of the Longwood Avenue, Boston, 8,10,11,17–19 Massachusetts 02115, USA. Prevention website). nociceptive nexus (FIG. 1), revealing the poten- 2FM Kirby Neurobiology Diverse pathological situations at different anato- tial for more fine-tuned targeting of acute and chronic Center Boston Children’s mical sites can lead to pain. Causes of pain include pain in different clinical conditions. Completely new Hospital, 300 Longwood cancer, inflammation or tissue injury, as well as injury therapeutic strategies targeting ion channels, enzymes Avenue, Boston, 4–8 Massachusetts 02115, USA. or lesions of the nervous system . Diverse chronic and G-protein-coupled receptors (GPCRs), often with 3Blue Therapeutics, Harvard widespread pain syndromes may also occur owing to human genetic validation, are emerging. In this Review, Innovation Launch Lab, 114 abnormal amplification states in the central nervous sys- we present these emerging mechanisms and assess tar- Western Avenue, Allston, tem (CNS)9–11. All of these can lead, through abnormal gets and agents in preclinical and early clinical stages of Massachusetts 02134, USA. Correspondence to A.S.Y. activity in nociceptive systems, to pain in the absence development that show promise for the development and C.J.W. of a stimulus (spontaneous pain), exaggerated responses of innovative analgesics (TABLES 1,2). [email protected]; to noxious stimuli (hyperalgesia) and pain evoked by Clifford.Woolf@childrens. normally innocuous stimuli (allodynia). Neurobiology of pain harvard.edu The heterogeneity of clinical pain conditions and The mechanisms that sustain and drive chronic pain doi:10.1038/nrd.2017.87 the complexity and multiplicity of underlying patho- (FIG. 1) have been exhaustively reviewed elsewhere7,10,17,20–23. Published online 9 Jun 2017 Corrected online 23 Jun 2017 physiological mechanisms has made it difficult to iden- In physiological situations, pain is a necessary protective and 6 Oct 2017 tify tractable targets with broad involvement — the response that is initiated by high-threshold peripheral NATURE REVIEWS | DRUG DISCOVERY VOLUME 16 | AUGUST 2017 | 545 ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. REVIEWS Box 1 | The challenges of preclinical models of pain Another driver for spontaneous pain in the absence of a peripheral stimulus is the ectopic activity of primary 255,256 Preclinical rodent efficacy models are essential for analgesic development , but sensory neurons (FIG. 1). Several voltage-gated sodium their predictive validity has been questioned owing to several high-profile programmes channels (Nav1.3 (REFS 27,28), Nav1.7 and Nav1.8 in which rodent behavioural readouts predicted analgesic effects that were absent in (REFS 29–34)), potassium channels (KCNQ), calcium humans. For example, fatty acid amide hydrolase (FAAH) inhibitors were found to be antinociceptive in a range of animal models, but compounds such as PF-04457845 channels (Cav2.2) and hyperpolarization-activated produced no analgesic effect in people with osteoarthritis despite lowering FAAH cyclic nucleotide-modulated channel (HCN) have been activity by >96%244. Similarly, NK1 (substance P) antagonists were shown to robustly implicated in the modulation of ectopic activity and reverse rodent nociceptive responses in the context of inflammation and nerve injury membrane excitability in sensory neurons, especially but failed to produce analgesia in subsequent clinical trials257. Nonetheless, many after peripheral nerve injury35–38. However, a direct rela- clinically used analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and tionship between such ectopic activity of primary sen- opioids, produce antinociceptive effects in rodents256, albeit typically at much higher sory neurons with spontaneous pain is yet to be proven, doses than those used in patients. mainly due to inconsistent results and the paucity of reli- Using animal models of pain to detect putative analgesics faces several challenges. able preclinical models, although live-cell imaging with First, how do you measure pain, a conscious subjective report of an unpleasant sensory genetically encoded activity reporters should change this. experience, when you have no access to how an animal feels? Second, are the models true surrogates for the conditions or diseases that commonly produce pain in patients? One major consequence of peripheral inflamma- Third, how do you eliminate the confounders of bias, observer-induced changes and tion is the hyperfunction of nociceptive transduction lack of reproducibility? And last, it is possible that drugs that target human proteins ion channels on the peripheral terminals of sensory may not be active on their rodent homologues. neurons. These channels are responsible for converting Effectively measuring pain is perhaps the most difficult challenge, as we can only noxious stimuli into inward currents. The peripheral measure outcomes that may correlate with some aspect of pain, such as withdrawal sensitization of these transducers and ion channels from a stimulus or learned avoidance from a situation that may be painful. For involved in membrane excitability leads to a reduction reflexive measures of pain, typically a brief stimulus lasting for seconds is applied to in the threshold for activation and hyperexcitability of 5,6 a part of an animal’s body and a response measured . This clearly bears little nociceptor sensory neurons17. However, peripheral sen- correspondence to the clinical situation of ongoing spontaneous pain. Attempts have sitization alone does not fully account for the prolonged been made to develop outcome measures that may reflect the presence of discomfort, but these require more effort and validation to make them robust and presence of pain, dynamic tactile allodynia, temporal useful255. Some classes of analgesics, such as opiates, can reduce nociceptive reflexes summation of pain and the spread of pain hypersensi- 26 at high doses; however, this does not mean that such reflexes have predictive validity tivity to non- injured tissue (secondary hyper algesia) . for all classes of analgesics. These features of pain hypersensitivity are the conse- Some disease surrogates, such
Load more

Recommended publications
  • 058574-2018-CPDD-Program-Final
    Hilton San Diego Bayfront Hotel Map BOARD OF DIRECTORS Alan J. Budney, PhD, President Sarah H. Heil, PhD Leonard Howell, PhD, Past-President Amy C. Janes, PhD Margaret Haney, PhD, President-Elect Geoffrey K. Mumford, PhD Jack Bergman, PhD, Treasurer Thomas E. Prisinzano, PhD Sandra D. Comer, PhD, Public Policy Officer Beatriz Rocha, MD, PhD Patrick M. Beardsley, PhD Stacey C. Sigmon, PhD Kathleen M. Carroll, PhD Mark A. Smith, PhD Marilyn E. Carroll, PhD William Stoops, PhD Howard D. Chilcoat, ScD Jennifer Tidey, PhD Timothy P. Condon, PhD Elise Weerts, PhD EXECUTIVE OFFICER Loretta P. Finnegan, MD DIRECTOR, EXECUTIVE OFFICE Ellen B. Geller, MA SCIENTIFIC PROGRAM COMMITTEE William W. Stoops, PhD, Chair Elise Weerts, PhD, Past-Chair Howard Chilcoat, ScD Danielle E. Ramo, PhD Theresa Franklin, PhD Sterling McPherson, PhD Kevin B. Freeman, PhD Gregory Collins, PhD Cassie Gipson-Reichardt, PhD Jillian Hardee, PhD Stephen Kohut, PhD Maria Parker, PhD, M.P.H. Loretta P. Finnegan, MD ex officio Ellen B. Geller, MA ex officio Save AsSave AsWord Word Doc Saturday, June 9, 2018 ISGIDAR Sapphire LP 8:00 - 5:00 PM NIDA INTERNATIONAL FORUM Sapphire DH 8:30 - 5:00 PM (PRE-REGISTRANTS ONLY) NIDA GRANT-WRITING Aqua C 1:00 - 5:00 PM REGISTRATION Sapphire NW Foyer 1:30 - 5:30 PM OPENING RECEPTION Promenade Plaza 7:00 - 9:00 PM Sunday, June 10, 2018 PLENARY PROGRAM Indigo BCFG 8:30 - 11:00 AM 8:30 Welcome CPDD President Alan J. Budney 8:45 Celebrating the 80th Annual Scientific Meeting of the Committee/College on Problems of Drug Dependence Loretta P.
    [Show full text]
  • Crowdsourcing Analysis of Off-Label Intervention Usage in Amyotrophic Lateral Sclersosis
    CROWDSOURCING ANALYSIS OF OFF-LABEL INTERVENTION USAGE IN AMYOTROPHIC LATERAL SCLERSOSIS A Thesis Presented to The Academic Faculty by Benjamin I. Mertens In Partial Fulfillment of the Requirements for the Degree B.S. in Biomedical Engineering with the Research Option in the Wallace H. Coulter School of Biomedical Engineering Georgia Institute of Technology Spring 2017 1 ACKNOWLEDGEMENTS I would like to thank my research advisor, Dr. Cassie Mitchell, first and foremost, for helping me through this long process of research, analysis, writing this thesis and the corresponding article to be submitted for peer-reviewed journal publication. There is no way I could have done this, or written it as eloquently without her. Next, I would like to acknowledge Grant Coan, Gloria Bowen, and Nathan Neuhart for all helping me on the road to writing this paper. Lastly, I would like to thank Dr. Lena Ting for her consultation as the faculty reader. 2 TABLE OF CONTENTS Page ACKNOWLEDGEMENTS 2 LIST OF TABLES 4 LIST OF FIGURES 5 LIST OF ABBREVIATIONS 6 SUMMARY 7 CHAPTERS 1 Philosophy 9 2 Crowdsourced Off-label Medications to Extend ALS Disease Duration 12 Introduction 12 Methodology 15 Results 18 Discussion 25 Tables 33 Figures 38 APPENDIX A: All Table 2 Appearance in Patients and Visits 44 APPENDIX B: All Table 3 Appearance in Patients and Visits 114 REFERENCES 129 3 LIST OF TABLES Page Table 1: Database Overview 33 Table 2: Ontology of Individual Medications 34 Table 3: Ontology of Intervention Groups 36 4 LIST OF FIGURES Page Figure 1: Relational circle
    [Show full text]
  • Practice Questions of Backlog Examination - 20 Questions (2M Each) Select Correct Answer for the Following Multiple Choice Questions
    Practice Questions of backlog examination - 20 Questions (2M each) Select correct answer for the following Multiple Choice Questions. Final Year B. Pharm. (Sem-VII) (CBSGS) Pharmaceutical Chemistry III 1. One of these is a HDAC inhibitor. a. Vorinostat b. Epalristat c. Imatinib d. Oxaliplatin 2. AZT, an antiviral agent is a a. Protease inhibitor b. Nonnucleoside RT inhibitor c. Nucleoside RT inhibitor d. Entry inhibitor 3. The sugar present in digitalis glycosides is a. Sucrose b. Glucose c. Digitoxose d. Galactose 4. The active metabolite of verapamil is a product of a. O-dealkylation b. C-dealkylation c. N-dealkylation d. Reduction 5. The epimer of Qunidine has the following activity a. Anti-diabetic b. Anti-malarial c. Analgesic d. Antihypertensive 6. N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl) acetamide is the IUPAC name of a. Furosemide b. Acetazolamide c. Methazolamide d. Thiazoleamide 7. Enalapril and captopril are a. ACE inhibitors b. Prodrugs c. Used in diarrhoea d. Used as a prodrug Practice Questions of backlog examination - 20 Questions (2M each) Select correct answer for the following Multiple Choice Questions. 8. The Phase -2 metabolite of one of these drugs is active a. Esmolol b. Prazocin c. Minoxidil d. Timolol 9. Which of following is anthranilic acid derivative? (a) Furosemide (b) Bumetanide (c) Ethacrynic acid (d) None 10. Aspirin is chemically a. A reverse ester of salicylic acid b. An amide of salicylic acid c. An ester of salicylic acid d. An imide of salicylic acid 11. The structure of 5-Fluorouracil, an anticancer agent has a. Purine nucleus b.
    [Show full text]
  • Fernandez-Sanchez Et Al
    Amino Acids (2002) 23: 31–36 DOI 10.1007/s00726-001-0106-6 Nefopam, an analogue of orphenadrine, protects against both NMDA receptor-dependent and independent veratridine-induced neurotoxicity M. T. Fernández-Sánchez 1, R. Díaz-Trelles 1, A. Groppetti 3, B. Manfredi 3, A. T. Brini 3, G. Biella 4,5, M. L. Sotgiu 5, and A. Novelli 1,2 1 Department of Biochemistry and Molecular Biology, University of Oviedo, Oviedo, Spain 2 Department of Psychology, University of Oviedo, Oviedo, Spain 3 Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy 4 Department of Science and Biomedical Technologies, University of Milan, Milan, Italy 5 Institute of Neuroscience and Bioimaging, CNR, Segrate, Italy Received June 29, 2001 Accepted August 6, 2001 Published online June 3, 2002 © Springer-Verlag 2002 Summary. Nefopam hyghochloride is a potent analgesic compound have demonstrated nefopam to be very effective in the commercialized in most Western Europe for 20 years, which pos- prevention of postoperative shivering in patients after sesses a profile distinct from that of opioids or anti-inflammatory drugs. Previous evidence suggested a central action of nefopam general anesthesia (Rosa et al., 1995) without affecting but the detailed mechanisms remain unclear. While, nefopam struc- the recovering time between the end of anesthesia and ture resembles that of orphenadrine, an uncompetitive NMDA extubation (Piper et al., 1999). Unpleasant adverse receptor antagonist, here we report that differently from effects during therapeutic use have been also reported orphenadrine, nefopam (100 µM) failed to protect cultured cerebel- lar neurons from excitotoxicity following direct exposure of neurons including dizziness, headache, nausea, vomiting and to glutamate.
    [Show full text]
  • Small Dose... Big Poison
    Traps for the unwary George Braitberg Ed Oakley Small dose... Big poison All substances are poisons; Background There is none which is not a poison. It is not possible to identify all toxic substances in a single The right dose differentiates a poison from a remedy. journal article. However, there are some exposures that in Paracelsus (1493–1541)1 small doses are potentially fatal. Many of these exposures are particularly toxic to children. Using data from poison control centres, it is possible to recognise this group of Poisoning is a frequent occurrence with a low fatality rate. exposures. In 2008, almost 2.5 million human exposures were reported to the National Poison Data System (NPDS) in the United Objective States, of which only 1315 were thought to contribute This article provides information to assist the general to fatality.2 The most common poisons associated with practitioner to identify potential toxic substance exposures in children. fatalities are shown in Figure 1. Polypharmacy (the ingestion of more than one drug) is far more common. Discussion In this article the authors report the signs and symptoms Substances most frequently involved in human exposure are shown of toxic exposures and identify the time of onset. Where in Figure 2. In paediatric exposures there is an over-representation clear recommendations on the period of observation and of personal care products, cleaning solutions and other household known fatal dose are available, these are provided. We do not discuss management or disposition, and advise readers products, with ingestions peaking in the toddler age group. This to contact the Poison Information Service or a toxicologist reflects the acquisition of developmental milestones and subsequent for this advice.
    [Show full text]
  • Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery
    fphar-07-00121 May 7, 2016 Time: 11:45 # 1 REVIEW published: 10 May 2016 doi: 10.3389/fphar.2016.00121 Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery Paola Imbrici1*, Antonella Liantonio1, Giulia M. Camerino1, Michela De Bellis1, Claudia Camerino2, Antonietta Mele1, Arcangela Giustino3, Sabata Pierno1, Annamaria De Luca1, Domenico Tricarico1, Jean-Francois Desaphy3 and Diana Conte1 1 Department of Pharmacy – Drug Sciences, University of Bari “Aldo Moro”, Bari, Italy, 2 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari “Aldo Moro”, Bari, Italy, 3 Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Bari, Italy In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, Edited by: disabling, or life-threatening. In spite of this, ion channels are the primary target of only Maria Cristina D’Adamo, University of Perugia, Italy about 5% of the marketed drugs suggesting their potential in drug discovery. The current Reviewed by: review summarizes the therapeutic management of the principal ion channelopathies Mirko Baruscotti, of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and University of Milano, Italy Adrien Moreau, pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion Institut Neuromyogene – École channels.
    [Show full text]
  • Chapter 151 – Antidepressants
    Crack Cast Show Notes – Skin and Soft Tissue Infections www.canadiem.org Chapter 151 – Antidepressants Key Concepts ❏ Although rarely used for depression, MAOIs are used in the treatment of Parkinson’s disease ❏ Because serious symptoms can occur after a lengthy latent period, patients with reported MAOI overdose should be admitted for 24 hours, regardless of symptoms. Symptoms are characterized by tachycardia, hypertension, and CNS changes, and later cardiovascular collapse. ❏ The primary manifestations of TCA toxicity are seizures, tachycardia, and intraventricular conduction delay. IV sodium bicarbonate should be administered for QRS prolongation. ❏ DO NOT USE PHYSOSTIGMINE IN TCA OVERDOSE ❏ SSRIs are comparatively benign in overdose. ❏ SNRI ingestions can result in seizures, tachycardia, and occasionally intraventricular conduction delay. ❏ The hallmark feature of serotonin syndrome is lower extremity rigidity (spasticity) with spontaneous or inducible clonus, especially at the ankles. ❏ Serotonin syndrome is primarily treated with supportive care, including discontinuation of the offending agent, and benzodiazepines. Sign Post 1) List 7 pharmacodynamic effects of cyclic antidepressants and describe the physiologic result 2) What are the ECG findings associated with TCA toxicity and what are their implications 3) Describe the management of TCA toxicity 4) What are the diagnostic criteria for Serotonin Syndrome? 5) How can you discern between NMS and Serotonin Syndrome? 6) What are the common meds causing Serotonin Syndrome? 7) Describe the management of Serotonin Syndrome 8) What is the primary risk of toxicity in Bupropion? 9) What are the 3 mechanisms by which MAOI toxicity can occur? And what is the clinical syndrome? 10) List 5 foods and 5 classes of meds that can interact to cause MAOI toxicity 11) Describe the management of MAOI toxicity.
    [Show full text]
  • STEMI Mimics V2
    S T E M I m i m i c s ; A m n e m o n i c ( v 2 . 0 ) S i m o n M a r k D a l e y ( 2 0 1 9 ) E levated / raised intracranial pressure (Such as SAH or haemorrhagic stroke) L eft bundle branch block arly repolarisation pattern (ERP) E Pericarditis ERP LBBB Aneurysm Brugada Ventricular hypertrophy / aneurysm S pontaneous coronary artery dissection (SCAD) Abdominal pathology (Pancreatitis / cholecystitis E mbolism (Pulmonary) T umor G rief (Takotsubo cardiomyopathy) E lectricity (Post DCCV) M yocarditis / Pericarditis Device (Ventricular paced rhythm) E lectrolytes (Hyperkalaemia / hypercalcaemia) N a+ (Sodium channelopathy; Brugada syndrome / sodium channel blocker) S pasm of the coronary arteries (Prinzmetal's / variant angina) T emperature (Hypothermia) T horacic aortic dissection May not be an exhaustive list; Clinical judgement must always be applied. Ventricular hypertrophy / aneurysm; Ventricular hypertrophy. Accounts for up to 25% of ED presentations with chest pain. The left ventricle hypertrophies in response to pressure secondary to conditions such as hypertension and aortic stenosis, as well as aortic regurgitation, mitral regurgitation, coarctation of the aorta, and hypertrophic cardiomyopathy. This leads to the following ECG features; Increased R wave amplitude in leads I, aVL and v4-v6. Increased S wave depth in leads III, aVR,v1-v3. The thickened LV wall leads to prolonged depolarisation, increased R wave peak time and delayed repolarisation (ST and T wave abnormalities) in the lateral leads. Diagnostic criteria (Sokolov-Lyon); S wave depth in v1 + tallest R wave height in v5-v6 >35mm. (Courtesy of LITFL) Ventricular hypertrophy / aneurysm; Ventricular aneurysm; Persistent ST segment elevation following an acute myocardial infarction.
    [Show full text]
  • Nav1.7 As a Pain Target
    ÔØ ÅÒÙ×Ö ÔØ NaV 1.7 as a pain target – from gene to pharmacology Irina Vetter, Jennifer R. Deuis, Alexander Mueller, Mathilde R. Israel, Hana Starobova, Alan Zhang, Lachlan Rash, Mehdi Mobli PII: S0163-7258(16)30241-8 DOI: doi:10.1016/j.pharmthera.2016.11.015 Reference: JPT 6999 To appear in: Pharmacology and Therapeutics Please cite this article as: Vetter, I., Deuis, J.R., Mueller, A., Israel, M.R., Starobova, H., Zhang, A., Rash, L. & Mobli, M., NaV 1.7 as a pain target – from gene to pharmacology, Pharmacology and Therapeutics (2016), doi:10.1016/j.pharmthera.2016.11.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT P&T #23131 Na V1.7 as a pain target – from gene to pharmacology Irina Vetter* 1,2 , Jennifer R. Deuis 1, Alexander Mueller 1, Mathilde R. Israel 1, Hana Starobova 1, Alan Zhang 3, Lachlan Rash 1,4 , Mehdi Mobli 3 1 Institute for Molecular Bioscience, Centre for Pain Research, The University of Queensland, St Lucia, Qld 4072, Australia 2 School of Pharmacy, The University of Queensland, Woolloongabba, Qld 4102, Australia 3 Centre for Advanced Imaging, The University of Queensland, St Lucia, Qld 4072, Australia 4 School of Biomedical Sciences, The University of Queensland, St Lucia, Qld 4072, Australia * Corresponding author.
    [Show full text]
  • Voltage-Gated Sodium Channels and Blockers: an Overview and Where Will They Go?*
    Current Medical Science 39(6):863-873,2019 DOICurrent https://doi.org/10.1007/s11596-019-2117-0 Medical Science 39(6):2019 863 Voltage-gated Sodium Channels and Blockers: An Overview and Where Will They Go?* Zhi-mei LI1, Li-xia CHEN2#, Hua LI1# 1Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China 2Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China Huazhong University of Science and Technology 2019 Summary: Voltage-gated sodium (Nav) channels are critical players in the generation and propagation of action potentials by triggering membrane depolarization. Mutations in Nav channels are associated with a variety of channelopathies, which makes them relevant targets for pharmaceutical intervention. So far, the cryoelectron microscopic structure of the human Nav1.2, Nav1.4, and Nav1.7 has been reported, which sheds light on the molecular basis of functional mechanism of Nav channels and provides a path toward structure-based drug discovery. In this review, we focus on the recent advances in the structure, molecular mechanism and modulation of Nav channels, and state updated sodium channel blockers for the treatment of pathophysiology disorders and briefly discuss where the blockers may be developed in the future. Key words: voltage-gated sodium channels; blockers; Nav channel structures; channelopathies Life did not come into existence until living In this review, we focus on voltage-gated organisms were enclosed by one or more membranes sodium (Nav) channels, which selectively conduct which cut them off from the chaotic world at a sodium ions movement in response to variations of molecular level.
    [Show full text]
  • Biased Agonism at Μ-Opioid Receptor
    Biased Agonism at µ-Opioid Receptor The Quest for Safer Analgesics Fabian August Line Project Thesis at the Faculty of Medicine UNIVERSITY OF OSLO 24.03.19 I II Biased agonism at µ-opioid receptor The Quest for Safer Analgesics Analgesic effect of µ-Opioid receptor stimulation is related to the G-protein, while the respiratory suppression is related to β-arrestin recruitment.(Schmid et al., 2017) Fabian August Line III IV Copyright Fabian A. Line 2019 Biased Agonism at µ-Opioid Receptor – The Quest for Safer Analgesics Fabian A. Line http://www.duo.uio.no Trykk: Reprosentralen, Universitetet i Oslo V VI Abstract Opioids are our most potent antinociceptive drugs, but their use is limited by adverse effects. Among the adverse effects are addiction, constipation and respiratory depression. In this thesis I review the current literature on biased µ-opioid receptor agonists and their potential for providing safer analgesia. Biased agonists activate one signaling effector over another. Among G-protein-coupled receptors, biased agonism is often used to denote an agonist that activates either G-protein-dependent signaling or β-arrestin-dependent signaling (G-protein-independent signaling). For the μ-opioid receptor, an agonist that activate the G-protein without recruiting β-arrestin-2 has been proposed to cause less respiratory depression, less addiction, less tolerance, less constipation and less opioid induced hyperalgesia. From the available literature I found substantial evidence for less respiratory depression by biased µ-opioid receptor agonists relative to classical opioids, while the data regarding constipation, addiction, tolerance and opioid induced hyperalgesia was less clear.
    [Show full text]
  • A High Throughput Screen Identifies Nefopam As Targeting Cell Proliferation in B-Catenin Driven Neoplastic and Reactive Fibroproliferative Disorders
    A High Throughput Screen Identifies Nefopam as Targeting Cell Proliferation in b-Catenin Driven Neoplastic and Reactive Fibroproliferative Disorders Raymond Poon1, Helen Hong1, Xin Wei2, James Pan3, Benjamin A. Alman1,4* 1 Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada, 2 Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada, 3 Donnelly Centre for Cellular and Molecular Research and Banting and Best Institute for Medical Research, University of Toronto, Toronto, Ontario, Canada, 4 Division of Orthopaedics, Department of Surgery, University of Toronto, Toronto, Ontario, Canada Abstract Fibroproliferative disorders include neoplastic and reactive processes (e.g. desmoid tumor and hypertrophic scars). They are characterized by activation of b-catenin signaling, and effective pharmacologic approaches are lacking. Here we undertook a high throughput screen using human desmoid tumor cell cultures to identify agents that would inhibit cell viability in tumor cells but not normal fibroblasts. Agents were then tested in additional cell cultures for an effect on cell proliferation, apoptosis, and b-catenin protein level. Ultimately they were tested in Apc1638N mice, which develop desmoid tumors, as well as in wild type mice subjected to full thickness skin wounds. The screen identified Neofopam, as an agent that inhibited cell numbers to 42% of baseline in cell cultures from b-catenin driven fibroproliferative disorders. Nefopam decreased cell proliferation and b-catenin protein level to 50% of baseline in these same cell cultures. The half maximal effective concentration in-vitro was 0.5 uM and there was a plateau in the effect after 48 hours of treatment.
    [Show full text]