DOCSLIB.ORG

IJBCP International Journal of Basic & Clinical Pharmacology Orexin

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
IJBCP International Journal of Basic & Clinical Pharmacology Orexin Print ISSN: 2319-2003 | Online ISSN: 2279-0780 IJBCP International Journal of Basic & Clinical Pharmacology DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20161493 Review Article Orexin receptors: a journey through their discovery to the development of suvorexant, the new sleeping pill Anandabaskar Nishanthi*, Mourouguessine Vimal, Selvarajan Sandhiya, Steven Aibor Dkhar JIPMER, Sri Manakula Vinayagar Medical College and ABSTRACT Hospital, Puducherry, India Orexin (OX) neuropeptides acting through G-protein coupled OX1 and OX2 Received: 29 March 2016 receptors are implicated in a variety of physiological roles including regulation Accepted: 27 April 2016 of feeding, sleep-wake cycle, energy metabolism and reward pathways. Accumulating experimental evidence indicates that orexins are wake promoting *Correspondence to: neuropeptides and deficits in orexinergic neurotransmission leads to narcolepsy, Dr. Anandabaskar Nishanthi, a debilitating sleep disorder. This has led to a search for orexin receptor agonists Email: nishanthi11189 for pharmacotherapy of narcolepsy. However, development of orexin receptor @gmail.com agonists are still in their infancy stage and it invokes further research to know whether it could turn into a reality. In addition, the role of orexin neuropeptides Copyright: © the author(s), in promoting arousal and wakefulness has generated considerable interest in publisher and licensee Medip developing orexin receptor antagonists for treatment of insomnia. This quest Academy. This is an open- was accomplished with the approval of suvorexant by United States food and access article distributed under drug administration in 2014. This remarkable discovery has opened a novel the terms of the Creative approach for treatment of insomnia through neuromodulation of orexin Commons Attribution Non- signaling. Hence this review focuses on the orexinergic system, their Commercial License, which physiological action and potential role as pharmacological targets. permits unrestricted non- commercial use, distribution, Keywords: OX receptors, Hypocretin receptors, Insomnia, Suvorexant, and reproduction in any Neuropeptide medium, provided the original work is properly cited. INTRODUCTION orexin-B. These peptide ligands were named after the greek word “orexis” meaning “appetite” since they were Two independent groups of researchers discovered the implicated in regulation of feeding behavior. Later it was orexin/hypocretin neuropeptides in 1998. De Lecea et al discovered that both orexins and hypocretins were similar working on wistar rats identified a hypothalamus specific neuropeptides and this finding ignited a debate on their mRNA coding for a precursor protein preprohypocretin naming system. In order to bring an end to this that on cleavage yielded two closely related proteins nomenclature debate and reach a consensus, the called hypocretin-1 and hypocretin-2.1 Hypocretins were international union of basic and clinical pharmacology 3 named so since they were selectively located in the gave the following recommendations. They proposed to neurons of hypothalamus and because of their similarity designate “hypocretin” for the gene and mRNA coding to the gut peptide “secretin”. Another team of researchers for the neuropeptides. The precursor protein and headed by Sakurai et al used reverse pharmacology processed peptides were named “prepro-orexin” and approach for deorphanization of several orphan G-protein “orexins A and B” respectively. Similarly, the G-protein coupled receptors.2 These screening experiments led to coupled receptors for these peptides were called as the discovery of orexin neuropeptides, orexin-A and “orexin receptors” and the genes that encode these www.ijbcp.com International Journal of Basic & Clinical Pharmacology | May-June 2016 | Vol 5 | Issue 3 Page 573 Nishanthi A et al. Int J Basic Clin Pharmacol. 2016 Jun;5(3):573-578 receptors were designated as “hypocretin receptor genes”. and Gi/o (inhibition of cAMP production).7 Studies on Although this nomenclature is confusing at first look cultured rat cortical neurons, show that orexin ligands especially to a novice in this field, it gives credit to the acting on OX2 receptors couple to Gi regulatory protein work of both the groups of scientists who discovered and inhibit cyclic AMP synthesis.8 A recent study on them. Chinese hamster ovarian cell lines has revealed other signaling mechanisms like activation of phospholipase D Orexins are neuropeptides selectively produced by a and release of arachidonic acid upon activation of OX1 group of neurons located in the dorsolateral part of the orexin receptors.9 hypothalamus. They are of two types namely orexin A and B, containing 33 and 28 amino acid peptides Orexins being excitatory neuropeptides, stimulation of respectively with 64% similarity to their amino acid their receptors lead to depolarization by the following sequences. They act on G-protein coupled receptors OX1 mechanisms; (i) activation of NSCC (non - selective and OX2 orexin receptors comprised of 425 and 444 cation channels), (ii) stimulation of NCX (sodium amino acids respectively. The OX2 receptors exhibit equal calcium exchanger) and (iii) inhibition of potassium 10 affinity for both orexin A and B, on the other hand OX1 channels which are active at rest. Although their receptors display tenfold higher affinity for orexin-A than signaling mechanisms have been elucidated, their orexin-B.2 physiological significance still remains elusive. Further studies are needed to clarify the signaling mechanisms, Immunological and molecular biological methods were second messengers involved in orexin pathway and their used to identify the distribution of orexinergic neurons physiological roles. This would give us the opportunity to and orexin receptors. The cell bodies of orexinergic understand the signaling mechanisms and provide a neurons are present mainly in the dorsolateral fruitful resource for drug discovery. hypothalamus, whereas their nerve fibres project widely in the central nervous system especially to the thalamus, Physiological role of orexinergic system hypothalamus, brain stem and spinal cord. There are about 50,000 to 80,000 orexinergic cells in the human Orexin neuronal activation promotes arousal and brain.4 The orexinergic neurons express norepinephrine, wakefulness by modulating the monoaminergic (locus serotonin, muscarinic acetylcholine, glutamate, GABA ceruleus, dorsal raphae nucleus and tuberomammillary (gamma aminobutyric acid), neuropeptide Y, ghrelin, nucleus) and cholinergic neurons (pedunculopontine leptin and cholecystokinin receptors. Thus, the orexin tegmental nucleus/ laterodorsal tegmental nucleus) of the neurons receive information about arousal and central nervous system. A study by Lee et al in rats wakefulness through glutamate, GABA, acetylcholine, demonstrated that while awake and when postural muscle norepinephrine and serotonin signaling; and feeding and tone was high, the orexin neurons discharge actively.11 metabolic state through neuropeptide Y, ghrelin, leptin Conversely, during sleep these neurons stopped firing and cholecystokinin signaling.5 signals. Hence, the authors concluded that orexinergic neurons stimulate wakefulness and increase tone of In the central nervous system, orexinergic neurons project muscle. Genetic ablation of the orexin containing neurons to the monoaminergic neurons promoting wakefulness in transgenic mice led to a phenotype similar to human like locus ceruleus (noradrenergic), dorsal raphe nucleus narcolepsy. These mice models were found to be obese (serotonergic) and tuberomamillary nucleus with hypophagia and ate less compared to their (histaminergic). These nuclei are richly endowed with the counterparts. This has led to a notion that orexinergic orexin receptors. Locus ceruleus neurons express mainly neurons could be involved in regulating energy 12 OX1 orexin receptors, tuberomammillary nuclei expresses metabolism along with regulation of feeding. OX2 orexin receptors and dorsal raphe nucleus expresses both OX1 and OX2 orexin receptors. Also cholinergic Apart from regulation of sleep wake cycle and appetite, neurons of pedunculopontine tegmental studies have demonstrated the role of orexins in activating nucleus/laterodorsal tegmental nucleus promote the brain reward systems. It was found that the vesicles of wakefulness and are richly furnished with OX1 orexin the presynaptic nerve terminals containing orexin receptors.5 neuropeptides housed co-transmitter dynorphin.13 Dynorphin decreases reward sensitivity and is associated Orexin signaling mechanisms with depression-like state. Later, it was discovered that orexin signaling through OX1 receptors facilitate reward The orexin receptor signaling mechanisms are highly by antagonizing the anti-reward effects of its co- complex. In a study by Karteris et al, it was found that the transmitter dynorphin.14 A recent study done by Flores et orexin receptors non-specifically couple to either of the al revealed the role of orexin receptors in extinction of four types of G-proteins, namely Gs, Gq , Go and Gi.6 A fear memories.15 This invokes further studies using orexin similar finding was observed in another study done in receptor antagonists as therapeutic targets for treatment of Chinese hamster ovary cell lines, where the OX1 orexin diseases associated with overwhelming and unreasonable receptors were reported to couple with Gs (stimulation of fear like phobia and post-traumatic stress disorders. cAMP production), Gq (activation
Load more

Recommended publications
  • Filorexant | Medchemexpress
    Inhibitors Product Data Sheet Filorexant • Agonists Cat. No.: HY-15653 CAS No.: 1088991-73-4 Molecular Formula: C₂₄H₂₅FN₄O₂ • Molecular Weight: 420.48 Screening Libraries Target: Orexin Receptor (OX Receptor) Pathway: GPCR/G Protein; Neuronal Signaling Storage: Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month SOLVENT & SOLUBILITY In Vitro DMSO : 100 mg/mL (237.82 mM; Need ultrasonic) Mass Solvent 1 mg 5 mg 10 mg Concentration Preparing 1 mM 2.3782 mL 11.8912 mL 23.7823 mL Stock Solutions 5 mM 0.4756 mL 2.3782 mL 4.7565 mL 10 mM 0.2378 mL 1.1891 mL 2.3782 mL Please refer to the solubility information to select the appropriate solvent. In Vivo 1. Add each solvent one by one: 10% DMSO >> 40% PEG300 >> 5% Tween-80 >> 45% saline Solubility: ≥ 2.5 mg/mL (5.95 mM); Clear solution 2. Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline) Solubility: ≥ 2.5 mg/mL (5.95 mM); Clear solution 3. Add each solvent one by one: 10% DMSO >> 90% corn oil Solubility: ≥ 2.5 mg/mL (5.95 mM); Clear solution BIOLOGICAL ACTIVITY Description Filorexant (MK-6096) is an orally bioavailable potent and selective reversible antagonist of OX1 and OX2 receptor(<3 nM in binding). IC₅₀ & Target Ki: < 3 nM(Orexin receptor)[1]. In Vitro In radioligand binding and functional cell based assays Filorexant (MK-6096) demonstrated potent binding and antagonism of both human OX(1)R and OX(2)R (<3 nM in binding, 11 nM in FLIPR), with no significant off-target activities against a panel Page 1 of 2 www.MedChemExpress.com of >170 receptors and enzymes.
    [Show full text]
  • Orexin Receptor Antagonists As Therapeutic Agents for Insomnia
    REVIEW ARTICLE published: 25 December 2013 doi: 10.3389/fphar.2013.00163 Orexin receptor antagonists as therapeutic agents for insomnia Ana C. Equihua 1, Alberto K. De La Herrán-Arita 2 and Rene Drucker-Colin 1* 1 Neuropatología Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, México 2 Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, CA, USA Edited by: Insomnia is a common clinical condition characterized by difficulty initiating or maintaining Christopher J. Winrow, Merck, USA sleep, or non-restorative sleep with impairment of daytime functioning. Currently, Reviewed by: treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) Matthew R. Ebben, Weill Medical and pharmacological therapy. Among pharmacological interventions, the most evidence College of Cornell University, USA Gabriella Gobbi, McGill University, exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although Canada concerns persist regarding their safety and their limited efficacy. The use of these Matt Carter, University of hypnotic medications must be carefully monitored for adverse effects. Orexin (hypocretin) Washington, USA neuropeptides have been shown to regulate transitions between wakefulness and Michihiro Mieda, Kanazawa University, Japan sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the *Correspondence: development of a new class of pharmacological agents that antagonize the physiological Rene Drucker-Colin, Departamento effects of orexin. The development of these agents may lead to novel therapies for de Neurociencias, Instituto de insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed Fisiología Celular, Universidad arousal, and motor balance difficulties). However, antagonizing a system that regulates Nacional Autónoma de México, Circuito exterior S/N, Apdo.
    [Show full text]
  • Preventive Report Appendix
    Title Authors Published Journal Volume Issue Pages DOI Final Status Exclusion Reason Nasal sumatriptan is effective in treatment of migraine attacks in children: A Ahonen K.; Hamalainen ML.; Rantala H.; 2004 Neurology 62 6 883-7 10.1212/01.wnl.0000115105.05966.a7 Deemed irrelevant in initial screening Seasonal variation in migraine. Alstadhaug KB.; Salvesen R.; Bekkelund SI. Cephalalgia : an 2005 international journal 25 10 811-6 10.1111/j.1468-2982.2005.01018.x Deemed irrelevant in initial screening Flunarizine, a calcium channel blocker: a new prophylactic drug in migraine. Amery WK. 1983 Headache 23 2 70-4 10.1111/j.1526-4610.1983.hed2302070 Deemed irrelevant in initial screening Monoamine oxidase inhibitors in the control of migraine. Anthony M.; Lance JW. Proceedings of the 1970 Australian 7 45-7 Deemed irrelevant in initial screening Prostaglandins and prostaglandin receptor antagonism in migraine. Antonova M. 2013 Danish medical 60 5 B4635 Deemed irrelevant in initial screening Divalproex extended-release in adolescent migraine prophylaxis: results of a Apostol G.; Cady RK.; Laforet GA.; Robieson randomized, double-blind, placebo-controlled study. WZ.; Olson E.; Abi-Saab WM.; Saltarelli M. 2008 Headache 48 7 1012-25 10.1111/j.1526-4610.2008.01081.x Deemed irrelevant in initial screening Divalproex sodium extended-release for the prophylaxis of migraine headache in Apostol G.; Lewis DW.; Laforet GA.; adolescents: results of a stand-alone, long-term open-label safety study. Robieson WZ.; Fugate JM.; Abi-Saab WM.; 2009 Headache 49 1 45-53 10.1111/j.1526-4610.2008.01279.x Deemed irrelevant in initial screening Safety and tolerability of divalproex sodium extended-release in the prophylaxis of Apostol G.; Pakalnis A.; Laforet GA.; migraine headaches: results of an open-label extension trial in adolescents.
    [Show full text]
  • Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
    CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products.
    [Show full text]
  • OREXIN ANTAGONISTS BELSOMRA (Suvorexant), DAYVIGO (Lemborexant)
    OREXIN ANTAGONISTS BELSOMRA (suvorexant), DAYVIGO (lemborexant) RATIONALE FOR INCLUSION IN PA PROGRAM Background Belsomra (suvorexant) and Dayvigo (lemborexant) are orexin receptor antagonists used to treat difficulty in falling and staying asleep (insomnia). Orexins are chemicals that are involved in regulating the sleep-wake cycle and play a role in keeping people awake (1-2). Regulatory Status FDA-approved indication: Orexin receptor antagonists are indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance (1-2). Orexin Antagonists are contraindicated in patients with narcolepsy (1-2). Orexin Antagonists are central nervous system (CNS) depressants that can impair daytime wakefulness even when used as prescribed. Medications that treat insomnia can cause next-day drowsiness and impair driving and other activities that require alertness. Orexin Antagonists can impair driving skills and may increase the risk of falling asleep while driving. People can be impaired even when they feel fully awake. Patients should also be made aware of the potential for next-day driving impairment, because there is individual variation in sensitivity to the drug (1-2). The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or mental illness that should be evaluated (1-2). Warnings and precautions that should be discussed with the patient on Orexin Antagonist therapy include adverse reactions on abnormal thinking and behavioral changes (such as amnesia, anxiety, hallucinations and other neuropsychiatric symptoms), complex behaviors (such as sleep- driving, preparing and eating food, or making phone calls), dose-dependent increase in suicidal ideation, and sleep paralysis which is the inability to move or speak for up to several minutes during sleep-wake transitions (1-2).
    [Show full text]
  • Merck & Co., Inc
    As filed with the Securities and Exchange Commission on February 25, 2021 UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D. C. 20549 _________________________________ FORM 10-K (MARK ONE) ☒ Annual Report Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934 For the Fiscal Year Ended December 31, 2020 OR ☐ Transition Report Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934 For the transition period from to Commission File No. 1-6571 _________________________________ Merck & Co., Inc. 2000 Galloping Hill Road Kenilworth New Jersey 07033 (908) 740-4000 New Jersey 22-1918501 (State or other jurisdiction of incorporation) (I.R.S Employer Identification No.) Securities Registered pursuant to Section 12(b) of the Act: Title of Each Class Trading Symbol(s) Name of Each Exchange on which Registered Common Stock ($0.50 par value) MRK New York Stock Exchange 1.125% Notes due 2021 MRK/21 New York Stock Exchange 0.500% Notes due 2024 MRK 24 New York Stock Exchange 1.875% Notes due 2026 MRK/26 New York Stock Exchange 2.500% Notes due 2034 MRK/34 New York Stock Exchange 1.375% Notes due 2036 MRK 36A New York Stock Exchange Number of shares of Common Stock ($0.50 par value) outstanding as of January 31, 2021: 2,530,315,668. Aggregate market value of Common Stock ($0.50 par value) held by non-affiliates on June 30, 2020 based on closing price on June 30, 2020: $195,461,000,000. Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.
    [Show full text]
  • Perspective Rxpipeline a Pharmacy
    A PHARMACY ON PERSPECTIVE THE RXPIPELINE Understanding changes in the medication market and their impact on cost and care. EnvisionPharmacies continuously monitors the drug pipeline. As treatment options change, we evaluate and share our perspective on the clinical benefits, cost-effectiveness and overall impact to payers, physicians and patients. Our Perspective on the Rx Pipeline report provides insights on what you should expect from your pharmacy partners to get patients the treatment they need. Included in this Edition } Clinical Pipeline } FDA Drug Approvals } New Indications } Upcoming and Recent Generic Launches } FDA Safety Update } Drug Shortages and Discontinuations 1 | A PHARMACY PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Clinical Pipeline PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market crizanlizumab SEG101 Manufacturer: Novartis Indication/Use: Sickle cell disease Dosage Form: Infusion Pipeline Stage: PDUFA 1/2020 Sickle cell disease is a debilitating genetic blood disorder that affects approximately 100,000 Americans.[1] Patients with sickle cell disease can suffer from vaso-occlusive crises (VOCs) that are incredibly painful and can cause irreversible tissue infarction and vasculopathy. VOCs are also associated with increased morbidity and mortality. [2] Hydroxyurea and pharmacy-grade L-glutamine are the only two FDA-approved pharmacotherapies currently available for the prevention of VOCs.[3] Crizanlizumab is a monoclonal antibody that works through selectin
    [Show full text]
  • Role of the Orexin Receptor System in Stress, Sleep and Cocaine Use
    Role of the orexin receptor system in stress, sleep and cocaine use NCT02785406 Version Date: 04/25/2017 IRB NUMBER: HSC-MS-16-0120 IRB APPROVAL DATE: 04/25/2017 Title: Role of the orexin receptor system in stress, sleep and cocaine use Principal Investigator: Scott D. Lane Co-Investigators: Joy M. Schmitz, Charles E. Green, Jin H. Yoon, Michael F. Weaver ABSTRACT Preclinical research has established important functions for the orexin system in mediating arousal/sleep, stress, and cue-induced reinstatement of drug taking (e.g., relapse). The role of stress/anxiety and drug cue reactivity in human drug relapse is well established, but to date, the role of the orexin system in modulating these phenomena has not been examined in humans with substance use disorders (e.g., cocaine). The goal of the present first-in-human study will be to examine the effects of an orexin antagonist (suvorexant) on interactions among stress/anxiety, sleep, and drug-cue reactivity. We will utilize a battery of highly sensitive, drug-specific, laboratory measures of drug cue reactivity (a relapse risk model), and well-established metrics of stress/anxiety and sleep. We hypothesize that antagonism of the orexin system will attenuate the link between (1) stress/anxiety and drug cue reactivity, and (2) sleep and drug cue reactivity. These results will elucidate a unique biochemical mechanism for understanding relapse, and provide a potential medication target for relapse prevention SCIENTIFIC IMPACT Given the promising preclinical data on the orexin system in modulating sleep, anxiety, and drug cue reactivity, this research project has high translational scientific value.
    [Show full text]
  • [14C]Lemborexant in Healthy Human Subjects and Characterization of Its Circulating Metabolites
    DMD Fast Forward. Published on November 3, 2020 as DOI: 10.1124/dmd.120.000229 This article has not been copyedited and formatted. The final version may differ from this version. Title Page Title: Disposition and Metabolism of [14C]Lemborexant in Healthy Human Subjects and Characterization of Its Circulating Metabolites Authors: Downloaded from Takashi Ueno, Tomomi Ishida, Jagadeesh Aluri, Michiyuki Suzuki, Carsten T. Beuckmann, Takaaki Kameyama, Shoji Asakura, Kazutomi Kusano dmd.aspetjournals.org Affiliation: Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.B., T.K., S.A., K.K.) Eisai Inc., Woodcliff Lake, NJ, U.S. (J.A.) EA Pharma Co., Ltd., Tokyo, Japan (M.S.) at ASPET Journals on September 24, 2021 1 DMD Fast Forward. Published on November 3, 2020 as DOI: 10.1124/dmd.120.000229 This article has not been copyedited and formatted. The final version may differ from this version. Running Title Page Running title: ADME properties of lemborexant in humans Corresponding Author: Takashi Ueno Downloaded from Drug Metabolism and Pharmacokinetics, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Phone: +81-29-847-5658 dmd.aspetjournals.org FAX: +81-29-847-5672 E-mail: [email protected] Number of text pages: 35 at ASPET Journals on September 24, 2021 Number of tables: 5 Number of figures: 3 Number of references: 23 Number of words in the Abstract: 249 Number of words in the Introduction: 665 Number of words in the Discussion: 1241 2 DMD Fast Forward. Published on November 3, 2020 as DOI: 10.1124/dmd.120.000229 This article has not been copyedited and formatted.
    [Show full text]
  • Clinical Pharmacology of Daridorexant, a Novel Dual Orexin Receptor Antagonist
    Clinical pharmacology of daridorexant, a novel dual orexin receptor antagonist Inauguraldissertation zur Erlangung der Würde eines Dr. sc. med. Vorgelegt der Medizinischen Fakultät der Universität Basel Von Clemens Mühlan aus 4055 Basel, Schweiz Basel, 2021 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Genehmigt von der Medizinischen Fakultät auf Antrag von Prof. Dr. Stephan Krähenbühl Prof. Dr. Matthias Liechti Dr. Alexander Jetter Dr. Jasper Dingemanse Basel, 24. Februar 2021 Dekan Prof. Dr. Primo Leo Schär 2 of 118 TABLE OF CONTENTS LIST OF ABBREVIATIONS AND ACRONYMS ............................................................4 ACKNOWLEDGEMENTS .................................................................................................8 SUMMARY .........................................................................................................................9 1 BACKGROUND AND INTRODUCTION ................................................................15 1.1 Insomnia .......................................................................................................15 1.2 The orexin system as a therapeutic target .....................................................18 1.3 Review of orexin receptor antagonists .........................................................20 1.4 Selective vs dual orexin receptor antagonism ..............................................23 1.5 Orexin receptor antagonists available in clinical practice ............................24 1.6 Orexin receptor
    [Show full text]
  • G Protein-Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
    [Show full text]
  • Overcoming Barriers to the Diagnosis and Treatment of Insomnia
    Overcoming Barriers to the Diagnosis and Treatment of Insomnia Thomas Roth, PhD Disclosure Note: This CME activity includes discussion about medications not approved by the US Food and Drug Administration and uses of medications outside of their approved labeling. CONTINUING MEDICAL EDUCATION LEARNING OBJECTIVES entity producing, marketing, re-selling enduring material for a maximum of 1.0 • Apply evidence-based diagnostic or distributing health care goods or ser- AMA PRA Category 1 credit(s)™. Physi- guidelines for patients who have clini- vices consumed by, or used on, patients. cians should claim only the credit com- cal features consistent with insomnia Mechanisms are in place to identify and mensurate with the extent of their par- resolve any potential conflict of interest ticipation in the activity. CME is available • Use evidence-based guidelines to prior to the start of the activity. In addi- September 1, 2020 to August 31, 2021. develop comprehensive treatment tion, any discussion of off-label, experi- plans that include cognitive-behav- mental, or investigational use of drugs or METHOD OF PARTICIPATION ioral therapy, pharmacologic treat- devices will be disclosed by the faculty. PHYSICIANS: To receive CME credit, ment, and combination therapies please read the journal article and, on to achieve optimal outcomes Dr. Roth discloses that he is on the advi- sory boards for Merck, Eisai, Jazz, Idorsia completion, go to www.pceconsortium. • Identify basic elements of cognitive- and Janssen. org/insomnia2 to complete the online behavioral therapy for insomnia post-test and receive your certificate of Gregory Scott, PharmD, RPh, editorial completion. • Differentiate among medications support, discloses he has no real or ap- FDA-approved for treating insomnia parent conflicts of interests to report.
    [Show full text]