DOCSLIB.ORG

A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides Neuroscience & Medicine, 2013, 4, 223-252 223 Published Online December 2013 (http://www.scirp.org/journal/nm) http://dx.doi.org/10.4236/nm.2013.44035 A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides Timur Kolomin1*, Maria Shadrina1, Petr Slominsky1, Svetlana Limborska1, Nikolay Myasoedov2 1Department of Molecular Basis of Human Genetics, Institute of Molecular Genetics Russian Academy of Sciences, Moscow, Russia; 2Department of Chemistry of Physiologically Active Compounds, Institute of Molecular Genetics Russian Academy of Sciences, Moscow, Russia. Email: *[email protected] Received July 15th, 2013; revised August 13th, 2013; accepted September 10th, 2013 Copyright © 2013 Timur Kolomin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ABSTRACT Natural regulatory peptides are biologically active compounds that are produced by various cells and provide a link among the main regulatory systems of the body. The field of research into the biologic activity of endogenous regula- tory peptides is extremely vast. These peptides affect the cardiovascular, immune, reproductive, endocrine, digestive, and other systems, alter energy metabolism, and are especially effective in the regulation of the central nervous system. Despite of the wide range of preventive and therapeutic effects of natural regulatory peptides and proteins, their applica- tion in clinical practice is difficult. This is primarily because of their extreme instability, as they are rapidly degraded by proteases of the gastrointestinal tract, blood, cerebrospinal fluid, and other biologic media. Compounds with higher sta- bility (i.e., a considerably longer half-life compared with that of natural molecules) and the ability to provide a direc- tional effect on the various body systems were obtained from modifications of endogenous regulatory peptides. Syn- thetic analogs of regulatory peptides, as a rule, contain only natural amino acids in their composition, and their biodeg- radation does not lead to the formation of toxic products; thus, they have fewer side effects. This review focuses on the consideration of two synthetic regulatory peptides, Semax and Selank, which were the bases for the creation of new drugs that are used effectively in the treatment of various diseases of the nervous system. The synthetic analog of an adrenocorticotropic hormone 4 - 10 fragment (ACTH4-10) Semax is a powerful neuroprotective agent that is particularly effective as a therapy for stroke. Selank was synthesized on the basis of the natural immunomodulator tuftsin. Selank is a powerful anxiolytic that is used as a therapy for generalized anxiety disorder and neurasthenia without sedative and muscle-relaxant effects. This review presents the results of research aimed at studying the influence of these peptides on the transcriptome of brain cells. The problems of drugs developed based on the clinical activities of Semax and Selank are discussed separately. Keywords: Semax; Selank; Regulatory Peptides; ACTH; Tuftsin; Neuroprotection; Nootropes; Anxiolytics 1. Introduction type of research. Peptide substances have been shown to be the direct regulators or mediators of the majority of The development and investigation of novel neurotropic physiological processes that occur in the body. In addi- drugs seem to be a challenging scientific problem for tion, regulatory peptides exhibit a vast range of biologic modern biology and pharmacology. Effective and safe activities. pharmacological remedies that stimulate the cognitive Neuropeptides represent important regulators of the functions of the brain and are neuroprotective in different central nervous system. However, the study of the bio- pathologies of the central nervous system are needed logic properties and mechanisms of action of the major urgently. The use of endogenous regulators of the body, known neuropeptides revealed that the clinical applica- especially regulatory peptides, as a basis for the devel- tion of the full-size molecules of these compounds was opment of drugs that meet the requirements stated above extremely complicated because of their instability inside provides one of the most promising directions for this the body and the fugacity of their effects. In this context, *Corresponding author. it becomes necessary to use them as a basis of the de- Open Access NM 224 A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides velopment of more stable synthetic molecules by various life compared with that of their precursor proteins, which modifications, which might be more effective compared is a significant precondition for the rapid interruption of with their prototypes, and at the same time, less harmful the signal processes mediated by these molecules, in case for use in clinical settings. they become unnecessary [2]. The aim of this review is to consider the characteristics The mechanism of action of regulatory peptides in a of two new-generation peptide preparations: the synthetic target cell is conditioned by their binding to special analog of an adrenocorticotropic hormone 4 - 10 frag- membrane receptors. All regulatory peptides are plei- ment (ACTH4-10), the neuroprotector and nootrope Se- otropic and are able to influence a number of physio- max, and the natural immunopeptide tuftsin analog, the logical functions, with individual functions being simul- anxiolytic and nootrope Selank. Large-scale studies of taneously regulated by several peptides. The fact that the range of biologic activity and mechanism of action of regulatory peptides that affect target cells are able to Semax and Selank revealed that the therapeutic potential regulate the release of other regulatory peptides, which, of drugs derived from these compounds was far from in turn, initiate the generation of a new wave of regula- being exhausted, and that new indications for their ap- tory peptides, represents an important feature of their plication could be discovered. mechanism of action. This allowed Ashmarin et al. to Success in the creation of drugs based on the synthetic pinpoint the existence of cascade processes in the regu- peptides Semax and Selank and the achievement of posi- latory peptide system that sustain the effect of a single tive outcomes from their clinical applications required administration of a peptide for a considerable period (up the study of their mechanisms of action, as this opens to several days), whereas the half-life of the peptide does new approaches to the creation of pharmacologically not exceed several minutes. This sets forth the functional important molecules and reveals the impact of new tar- continuum of regulatory peptides that participate in the gets for the directed regulation of cellular functions in transfer of information among the systems of the body health and disease. (its organs, tissues, cell groups, and individual cells), thereby regulating their activity and integrating their 2. Natural and Synthetic Regulatory performance into a unity. Thus, the regulatory-peptide Peptides system is involved in the regulation of virtually all Regulatory peptides are universal endogenous biologic physiological responses of the body, and maintains the regulators of cellular functions in the body. They are part homeostasis of all of its systems [3-6]. of the most complicated system of specialized signaling All cells of the body permanently synthesize, and molecules, of which the principal function is the integra- support the required levels of, regulatory peptides. How- tion of the nervous, endocrine, and immune systems to ever, their biosynthesis undergoes changes in the pres- form a united functional continuum. ence of broken homeostasis. A similar instability occurs Extensive investigation of regulatory peptides began in during adaptive responses to the background of physical the 1970s after a team of Dutch researchers headed by or/and emotional strain, predisease conditions, etc., David de Wied demonstrated that the adrenocorticotropic thereby preventing the disturbance of the functional bal- hormone and its fragments affected the learning of ani- ance, which is an indication that the regulation of the mals [1]. Currently, over 9000 regulatory peptides that metabolism of endogenous peptides occurs at the cellular differ in both structure and properties have been de- level (transcription, translation, and posttranslation proc- scribed, the majority of which contain from 2 to 50 essing), at the tissue level (secretion and inactivation of amino acid residues and belong to the group of oligopep- regulatory peptides), and at the level of the body as a tides with no more than 20 amino acids or to the group of whole [7]. polypeptides with 20 to 100 amino acid residues. The classification of regulatory peptides takes into ac- Posttranslational processing is one of the main path- count their chemical and physiological structure and their ways of regulatory-peptide formation in the body, via origin. One of the main difficulties in classifying these which they are isolated from the physiologically inactive molecules lies in their multifunctional character, which precursor proteins with the help of specialized enzymes- does not allow one or even several functions to be estab- proteases. In some cases, a single precursor protein gives lished in a substrate. Considering the physiological and rise
Load more

Recommended publications
  • (12) United States Patent (10) Patent No.: US 8,148,546 B2 Schuster Et Al
    US008148546B2 (12) United States Patent (10) Patent No.: US 8,148,546 B2 Schuster et al. (45) Date of Patent: Apr. 3, 2012 (54) TETRAHYDROCARBAZOLE DERIVATIVES (58) Field of Classification Search .................. 548/448: ASLGANDS OF G-PROTEIN COUPLED 51474 11 RECEPTORS See application file for complete search history. (75) Inventors: Tilmann Schuster, Grossostheim (DE); Klaus Paulini, Maintal (DE); Peter (56) References Cited Schmidt, Schoeneck (DE); Silke Baasner, Schoeneck (DE); Emmanuel FOREIGN PATENT DOCUMENTS Polymeropoulos, Frankfurt (DE); WO WO O3051837 * 6, 2003 Eckhard Guenther, Maintal (DE); WO WO 2006005484 * 1, 2006 Michael Teifel, Weiterstadt (DE) OTHER PUBLICATIONS (73) Assignee: AEterna Zentaris GmbH, Frankfurt Kubinyi (3D QSAR in Drug Design: Ligand-Protein Interactions and (DE) Molecular Similarity, vol. 2-3, Springer, 1998, 800 pages), TOC, pp. 243-244 provided.* *) NotOt1Ce: Subjubject to anyy d1Sclaimer,disclai theh term off thisthi Tatsuta et al. (Bioorg. Med. Chem. Lett. 15 (2005) 2265-2269).* patent is extended or adjusted under 35 Wermuth, The Practice of Medicinal Chemsitry, 2d ed. (2003), 768 U.S.C. 154(b) by 852 days. pages, chs. 9-10 provided.* CAPLUS Abstract of WO O3051837.* (21) Appl. No.: 12/109,479 * cited by examiner (22) Filed: Apr. 25, 2008 (65) Prior Publication Data Primary Examiner — Robert Havlin (74) Attorney, Agent, or Firm — Oblon, Spivak, US 2009/O 170783 A1 Jul. 2, 2009 McClelland, Maier & Neustadt, L.L.P. Related U.S. Application Data (60) Provisional application No. 60/914,424, filed on Apr. (57) ABSTRACT 27, 2007. The present invention provides novel tetrahydrocarbazole compounds according to formula (I) as ligands of G-protein (30) Foreign Application Priority Data coupled receptors (GPCR) which are useful in the treatment and/or prophylaxis of physiological and/or pathological con Apr.
    [Show full text]
  • Yerevan State Medical University After M. Heratsi
    YEREVAN STATE MEDICAL UNIVERSITY AFTER M. HERATSI DEPARTMENT OF PHARMACY Balasanyan M.G. Zhamharyan A.G. Afrikyan Sh. G. Khachaturyan M.S. Manjikyan A.P. MEDICINAL CHEMISTRY HANDOUT for the 3-rd-year pharmacy students (part 2) YEREVAN 2017 Analgesic Agents Agents that decrease pain are referred to as analgesics or as analgesics. Pain relieving agents are also called antinociceptives. An analgesic may be defined as a drug bringing about insensibility to pain without loss of consciousness. Pain has been classified into the following types: physiological, inflammatory, and neuropathic. Clearly, these all require different approaches to pain management. The three major classes of drugs used to manage pain are opioids, nonsteroidal anti-inflammatory agents, and non opioids with the central analgetic activity. Narcotic analgetics The prototype of opioids is Morphine. Morphine is obtained from opium, which is the partly dried latex from incised unripe capsules of Papaver somniferum. The opium contains a complex mixture of over 20 alkaloids. Two basic types of structures are recognized among the opium alkaloids, the phenanthrene (morphine) type and the benzylisoquinoline (papaverine) type (see structures), of which morphine, codeine, noscapine (narcotine), and papaverine are therapeutically the most important. The principle alkaloid in the mixture, and the one responsible for analgesic activity, is morphine. Morphine is an extremely complex molecule. In view of establish the structure a complicated molecule was to degrade the: compound into simpler molecules that were already known and could be identified. For example, the degradation of morphine with strong base produced methylamine, which established that there was an N-CH3 fragment in the molecule.
    [Show full text]
  • Information to Users
    The direct and modulatory antinociceptive actions of endogenous and exogenous opioid delta agonists Item Type text; Dissertation-Reproduction (electronic) Authors Vanderah, Todd William. Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 04/10/2021 00:14:57 Link to Item http://hdl.handle.net/10150/187190 INFORMATION TO USERS This ~uscript }las been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely. event that the author did not send UMI a complete mannscript and there are missing pages, these will be noted Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginnjng at the upper left-hand comer and contimJing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy.
    [Show full text]
  • Supplementary Digital Content REVIEW of ANXIETY MODELS USED in 2010-2011. Type of the Study. Here We Cathegorize the Study Accor
    Supplementary digital content REVIEW OF ANXIETY MODELS USED IN 2010-2011. LEGEND Type of the study. Here we cathegorize the study according to its major aim or major finding as follows: anxiogenic effects, the compound had effects opposite to expectations; detection of anxiolytic effect, anxiolytic effects were noticed but no suggestion was formulated for use as anxiolytics; established anxiolytic, well-known anxiolytics studied for various reasons; no effect on anxiety, the compound did not fulfil expectations; mechanism, studies employing anxiolytic treatments but addressing developmental issues, neural mechanisms, drug interactions etc.; putative novel anxiolytic, the authors suggested the compound for anxiolytic drug development; (H), the tested compound was an herbal extract; (Ho), purified or synthesized compound of herbal origin. Anxiety tests. The tests listed in Table 1 were considered 'classical' for the reasons specified in the Abstract. Modifier. Tests are sometimes performed under unconventional conditions to induce heightened levels of anxiety and by this to icrease the translational value of the test. Procedures that altered (usually increased) anxiety levels normally shown in the given test were categorized as follows. chemical, hormonal or pharmacological treatments (e.g. ovarectomy, drug administration in adolescence, etc.); condition, modified testing conditions (e.g. high lighting, no habituation to the testing room, etc.); neural, treatments that affect neural functions (e.g. brain lesions, inhibited neurogenesis); selection, subjects from selection lines, specific strains, etc; stress, subjects exposed to stressors with long-lasting consequences (e.g. chronic immobility, drug withdrawal, etc); subject, the use of specific subjects classes (aged subjects, females, etc.); transgenic, the effects of drugs were studied in genetically engineered subjects.
    [Show full text]
  • Enkephalin Degradation in Serum of Patients with Inflammatory Bowel Diseases
    Pharmacological Reports 71 (2019) 42–47 Contents lists available at ScienceDirect Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep Original article Enkephalin degradation in serum of patients with inflammatory bowel diseases a, a b Beata Wilenska *, Dagmara Tymecka , Marcin Włodarczyk , b c Aleksandra Sobolewska-Włodarczyk , Maria Wisniewska-Jarosinska , d e b a,d, Jolanta Dyniewicz , Árpád Somogyi , Jakub Fichna , Aleksandra Misicka * a Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warszawa, Poland b Department of Biochemistry, Medical University of Lodz, Łódz, Poland c Department of Gastroenterology, Medical University of Lodz, Łódz, Poland d Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Science, Warszawa, Poland e Campus Chemical Instrumentation Centre (CCIC), The Ohio State University, Columbus, OH, USA A R T I C L E I N F O A B S T R A C T Article history: Background: Inflammatory bowel diseases (IBD) are a group of chronic and recurrent gastrointestinal Received 18 April 2018 disorders that are difficult to control. Recently, a new IBD therapy based on the targeting of the Received in revised form 10 June 2018 endogenous opioid system has been proposed. Consequently, due to the fact that endogenous Accepted 1 August 2018 enkephalins have an anti-inflammatory effect, we aimed at investigating the degradation of serum Available online 2 August 2018 enkephalin (Met- and Leu-enkephalin) in patients with IBD. Methods: Enkephalin degradation in serum of patients with IBD was characterized using mass Keywords: spectrometry methods. Calculated half-life (T1/2) of enkephalins were compared and correlated with the Inflammatory bowel diseases disease type and gender of the patients.
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Semax Item No. 27719 CAS Registry No.: 80714-61-0 N Formal Name: L-methionyl-L-α-glutamyl- N H S L-histidyl-L-phenylalanyl-L- H2N prolylglycyl-L-proline O Synonym: ACTH4-7-PGP N H N N O MF: C37H51N9O10S O FW: 813.9 H N OH N O H Purity: ≥95% N O O O Supplied as: A solid H Storage: -20°C O HO Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Semax is supplied as a solid. A stock solution may be made by dissolving the semax in the solvent of choice, which should be purged with an inert gas. Semax is soluble in organic solvents such as DMSO and dimethyl formamide. The solubility of semax in these solvents is approximately 5 and 1 mg/ml, respectively. Further dilutions of the stock solution into aqueous buffers or isotonic saline should be made prior to performing biological experiments. Ensure that the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. Organic solvent-free aqueous solutions of semax can be prepared by directly dissolving the solid in aqueous buffers. The solubility of semax in PBS, pH 7.2, is approximately 10 mg/ml. We do not recommend storing the aqueous solution for more than one day. Description Semax is a synthetic peptide analog of adrenocorticotropic hormone (ACTH) (4-10) (Item No. 27106) that has neuroprotective, analgesic, and anxiolytic properties.1-3 In vivo, semax (0.3 mg/kg) reduces cortical nitric oxide (NO) production and the number of neurological disturbances, such as seizures, falling, and twisting, in a rat model of global ischemia.1 It decreases acetic acid-induced writhing and nociception in a hind paw compression test in mice when administered at doses ranging from 0.015 to 0.5 mg/kg.2 Semax also increases time spent in the open arms in the elevated plus maze, indicating anxiolytic activity, in a rat model of maternal deprivation-induced anxiety.3 References 1.
    [Show full text]
  • Effects of Semax on Dopaminergic and Serotoninergic Systems of the Brain K
    Doklady Biological Sciences, Vol. 394, 2004, pp. 1–3. Translated from Doklady Akademii Nauk, Vol. 394, No. 1, 2004, pp. 130–132. Original Russian Text Copyright © 2004 by Eremin, Kudrin, Grivennikov, Miasoedov, Rayevsky. PHYSIOLOGY Effects of Semax on Dopaminergic and Serotoninergic Systems of the Brain K. O. Eremin*, V. S. Kudrin*, I. A. Grivennikov**, Academician N. F. Miasoedov**, and K. S. Rayevsky* Received June 11, 2003 Short-term effects of the synthetic nootropic peptide in rats and simultaneously raises the intracellular level Semax on the content and metabolism of monoamines of dopamine in the striatum [6]. in the brain of C57/Bl6 mice and Sprague–Dawley rats The goal of this study was to examine the effects of were studied. Intraperitoneal injection of Semax at a Semax on the neurochemical parameters of the dopam- dose of 0.15 mg/kg caused an increase in the tissue con- inergic and serotoninergic systems of the animal brain. centrations of 5-hydroxyindoleacetic acid (5-HIAA) in Semax was administered at a dose of 0.15 mg per kilo- the hypothalamus and striatum of mice 0.5 and 2 h after gram body weight to ë57/Bl6 mice, and their hypothal- the injection. Using brain microdialysis, we detected amus and striatum were analyzed for tissue levels of increased levels of extracellular 5-HIAA in the striatum dopamine (DA) and its metabolites 3,4-dihydroxyphe- of freely moving rats 1 h after administration of 0.15 or nylacetic acid (DOPAC) and homovanillic acid (HVA), 0.6 mg/kg Semax. The effect lasted for an additional as well as serotonin (or 5-hydroxytriptamine, 5-HT) 3 h.
    [Show full text]
  • PRODUCT INFORMATION Spinorphin Item No
    PRODUCT INFORMATION Spinorphin Item No. 29914 NH CAS Registry No.: 137201-62-8 Formal Name: L-leucyl-L-valyl-L-valyl-L-tyrosyl-L- O H O N prolyl-L-tryptophyl-L-threonine N OH O N H Synonyms: Leu-Val-Val-Tyr-Pro-Trp-Thr, O OH H LVVYPWT O O N MF: C45H64N8O10 N N O FW: 877.0 H H NH2 Purity: ≥95% UV/Vis.: λmax: 222 nm Supplied as: A crystalline solid Storage: -20°C OH Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Spinorphin is supplied as a crystalline solid. A stock solution may be made by dissolving the spinorphin in the solvent of choice, which should be purged with an inert gas. Spinorphin is soluble in organic solvents such as DMSO and dimethyl formamide. The solubility of spinorphin in these solvents is approximately 30 mg/ml. Description Spinorphin is a heptapeptide inhibitor of the enkephalin-degrading enzymes aminopeptidase, dipeptidyl aminopeptidase, angiotensin-converting enzyme (ACE), and enkephalinase (IC50s = 3.3, 1.4, 2.4, and 10 µg/ml, respectively, for monkey brain enzymes).1 It is selective for these enzymes over human serum aminopeptidase A (IC50 = >100 µg/ml), as well as porcine kidney aminopeptidase B, aminopeptidase M, dipeptidyl peptidase 1 (DPP-1), DPP-2, DPP-3, and DPP-4 (IC50s = >55 µg/ml for all). Spinorphin inhibits chemotaxis, production of reactive oxygen species (ROS), and exocytosis of glucuronidase and collagenase in polymorphonuclear neutrophils (PMNs). It potentiates enkephalin-induced action potentials in rat hippocampal slices.
    [Show full text]
  • Screening of 109 Neuropeptides on Asics Reveals No Direct Agonists
    www.nature.com/scientificreports OPEN Screening of 109 neuropeptides on ASICs reveals no direct agonists and dynorphin A, YFMRFamide and Received: 7 August 2018 Accepted: 14 November 2018 endomorphin-1 as modulators Published: xx xx xxxx Anna Vyvers, Axel Schmidt, Dominik Wiemuth & Stefan Gründer Acid-sensing ion channels (ASICs) belong to the DEG/ENaC gene family. While ASIC1a, ASIC1b and ASIC3 are activated by extracellular protons, ASIC4 and the closely related bile acid-sensitive ion channel (BASIC or ASIC5) are orphan receptors. Neuropeptides are important modulators of ASICs. Moreover, related DEG/ENaCs are directly activated by neuropeptides, rendering neuropeptides interesting ligands of ASICs. Here, we performed an unbiased screen of 109 short neuropeptides (<20 amino acids) on fve homomeric ASICs: ASIC1a, ASIC1b, ASIC3, ASIC4 and BASIC. This screen revealed no direct agonist of any ASIC but three modulators. First, dynorphin A as a modulator of ASIC1a, which increased currents of partially desensitized channels; second, YFMRFamide as a modulator of ASIC1b and ASIC3, which decreased currents of ASIC1b and slowed desensitization of ASIC1b and ASIC3; and, third, endomorphin-1 as a modulator of ASIC3, which also slowed desensitization. With the exception of YFMRFamide, which, however, is not a mammalian neuropeptide, we identifed no new modulator of ASICs. In summary, our screen confrmed some known peptide modulators of ASICs but identifed no new peptide ligands of ASICs, suggesting that most short peptides acting as ligands of ASICs are already known. Acid-sensing ion channels form a small family of proton-gated ion channels that belongs to the degenerin/epi- thelial Na+ channel (DEG/ENaC) gene family1.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,345,661 B2 Adler Et Al
    USOO9345661 B2 (12) United States Patent (10) Patent No.: US 9,345,661 B2 Adler et al. (45) Date of Patent: May 24, 2016 (54) SUBCUTANEOUSANTI-HER2 ANTIBODY FOREIGN PATENT DOCUMENTS FORMULATIONS AND USES THEREOF CL 2756-2005 10/2005 CL 561-2011 3, 2011 (75) Inventors: Michael Adler, Riehen (CH); Ulla CL 269-2012 1, 2012 Grauschopf, Riehen (CH): CN 101163717 4/2008 Hanns-Christian Mahler, Basel (CH): CN 101370525 2, 2009 Oliver Boris Stauch, Freiburg (DE) EP O590058 B1 11, 2003 EP 1516628 B1 3, 2005 (73) Assignee: Genentech, Inc., South San Francisco, EP 1603541 11, 2009 JP 2007-533631 11, 2007 CA (US) JP 2008-5075.20 3, 2008 JP 2008-528638 T 2008 (*) Notice: Subject to any disclaimer, the term of this JP 2009-504142 2, 2009 patent is extended or adjusted under 35 JP 2009/055343 4/2009 U.S.C. 154(b) by 0 days. KR 2007-0068385 6, 2007 WO 93.21319 A1 10, 1993 WO 94/OO136 A1 1, 1994 (21) Appl. No.: 12/804,703 WO 97.048O1 2, 1997 WO 98.22136 5, 1998 (22) Filed: Jul. 27, 2010 WO 99.57134 11, 1999 WO 01.00245 A2 1, 2001 (65) Prior Publication Data WO 2004/078140 9, 2004 WO 2005/023328 3, 2005 US 2011 FOO44977 A1 Feb. 24, 2011 WO 2005/037992 A2 4/2005 WO 2005,117986 12/2005 (30) Foreign Application Priority Data WO WO 2005,117986 A2 * 12/2005 WO 2006/044908 A2 4/2006 Jul. 31, 2009 (EP) ..................................... 0.9167025 WO 2006/09 1871 8, 2006 WO 2007 O24715 3, 2007 (51) Int.
    [Show full text]
  • Neprilysin Controls the Synaptic Activity of Neuropeptides in the Intercalated Cells of the Amygdala
    Molecular Pharmacology Fast Forward. Published on June 30, 2020 as DOI: 10.1124/mol.119.119370 This article has not been copyedited and formatted. The final version may differ from this version. Neprilysin controls the synaptic activity of neuropeptides in the intercalated cells of the amygdala Authors: Gregoriou GC, Patel SD, Winters BL, Bagley EE Primary laboratory of origin: Discipline of Pharmacology & Charles Perkins Centre, Charles Perkins Centre D17, Downloaded from University of Sydney, Camperdown, NSW, 2006, Australia. molpharm.aspetjournals.org at ASPET Journals on October 1, 2021 1 Molecular Pharmacology Fast Forward. Published on June 30, 2020 as DOI: 10.1124/mol.119.119370 This article has not been copyedited and formatted. The final version may differ from this version. Running title: Neuropeptides degradation in the amygdala Corresponding author: Elena Bagley Address: Discipline of Pharmacology & Charles Perkins Centre, Charles Perkins Centre D17, University of Sydney, Camperdown, NSW, 2006, Australia. Telephone: 61 2 93514895 Fax: N/A E-mail: [email protected] Number of pages: 31 Downloaded from Number of figures: 3 Number of references: 56 Words in abstract: 245 molpharm.aspetjournals.org Words in introduction: 486 Words in discussion: 844 Abbreviations: at ASPET Journals on October 1, 2021 ACE: angiotensin-converting enzyme ACSF: artificial cerebrospinal fluid APN: aminopeptidase N BLA: basolateral amygdala CNS: central nervous system DOR: δ-opioid receptor EPSC: excitatory post‐synaptic currents MOR: µ-opioid receptor met-enk: methione enkephalin NEP: neprilysin N/OFQ: Nociceptin/Orphanin FQ PI: peptidase inhibitors PPR: paired pulse ratio 2 Molecular Pharmacology Fast Forward. Published on June 30, 2020 as DOI: 10.1124/mol.119.119370 This article has not been copyedited and formatted.
    [Show full text]
  • The Inhibition of Enkephalin Catabolism by Dual Enkephalinase Inhibitor: a Novel Possible Therapeutic Approach for Opioid Use Disorders
    Alvarez-Perez Beltran (Orcid ID: 0000-0001-8033-3136) Maldonado Rafael (Orcid ID: 0000-0002-4359-8773) THE INHIBITION OF ENKEPHALIN CATABOLISM BY DUAL ENKEPHALINASE INHIBITOR: A NOVEL POSSIBLE THERAPEUTIC APPROACH FOR OPIOID USE DISORDERS ALVAREZ-PEREZ Beltran1*, PORAS Hervé 2*, MALDONADO Rafael1 1 Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, c/Dr Aiguader 88, 08003 Barcelona, Spain, 2 Pharmaleads, Paris BioPark, 11 Rue Watt, 75013 Paris, France *Both authors participated equally to the manuscript Correspondence: Rafael Maldonado, Laboratori de Neurofarmacologia, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona (PRBB), c/Dr. Aiguader, 88, 08003 Barcelona, Spain. E-mail: [email protected] ABSTRACT Despite the increasing impact of opioid use disorders on society, there is a disturbing lack of effective medications for their clinical management. An interesting innovative strategy to treat these disorders consists in the protection of endogenous opioid peptides to activate opioid receptors, avoiding the classical opioid-like side effects. Dual Enkephalinase Inhibitors (DENKIs) physiologically activate the endogenous opioid system by inhibiting the enzymes responsible for the breakdown of enkephalins, protecting endogenous enkephalins, increasing their half-lives and physiological actions. The activation of opioid receptors by the increased enkephalin levels, and their well-demonstrated safety, suggest that DENKIs could represent a novel analgesic therapy and a possible effective treatment for acute opioid withdrawal, as well as a promising alternative to opioid substitution therapy minimizing side effects. This new pharmacological class of compounds could bring effective and safe medications avoiding the This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record.
    [Show full text]