DOCSLIB.ORG

A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans Cellular Physiology Cell Physiol Biochem 2018;45:88-107 DOI: 10.1159/00048622510.1159/000486225 © 2018 The Author(s).© 2018 Published The Author(s) by S. Karger AG, Basel Published online: online: January January 08, 08, 2018 2018 www.karger.com/cpbPublished by S. Karger AG, Basel 88 and Biochemistry www.karger.com/cpb Yi et al.: NPY Receptors in Metabolic Diseases Accepted: October 17, 2017 This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 Interna- tional License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Review A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans Min Yia,b,c Hekai Lia,b,c Zhiye Wua,b,c Jianyun Yana,b,c Qicai Liua,b,c Caiwen Oua,b,c Minsheng Chena,b,c aDepartment of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University; Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University; bGuangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease; cSino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, P. R. China Key Words Neuropeptide Y • Neuropeptide Y receptors • G-protein-coupled receptors (GPCRs) • Metabolic diseases Abstract Human neuropeptide Y (hNPY) is one of the most widely expressed neurotransmitters in the human central and peripheral nervous systems. It consists of 36 highly conserved amino acid residues, and was first isolated from the porcine hypothalamus in 1982. While it is the most recently discovered member of the pancreatic polypeptide family (which includes neuropeptide Y, gut-derived hormone peptide YY, and pancreatic polypeptide), NPY is the most abundant peptide found in the mammalian brain. In order to exert particular functions, NPY needs to bind to the NPY receptor to activate specific signaling pathways. NPY receptors belong to the class A or rhodopsin-like G-protein coupled receptor (GPCR) family and signal via cell-surface receptors. By binding to GPCRs, NPY plays a crucial role in various biological processes, including cortical excitability, stress response, food intake, circadian rhythms, and cardiovascular function. Abnormal regulation of NPY is involved in the development of a wide range of diseases, including obesity, hypertension, atherosclerosis, epilepsy, metabolic disorders, and many cancers. Thus far, five receptors have been cloned from mammals (Y1, Y2, Y4, Y5, and y6), but only four of these (hY1, hY2, hY4, and hY5) are functional in humans. In this review, we summarize the structural characteristics of human NPY receptors and their role in metabolic diseases. © 2018 The Author(s) Published by S. Karger AG, Basel Introduction Neuropeptide Y is widely expressed in the human central and peripheral nervous sys- tem. This is a highly conserved 36-amino acid peptide which was first isolated from porcine Minsheng Chen Laboratory of Heart Center, Zhujiang hospital, Southern Medical University, andhypothalamus Caiwen Ou in 1982 [1]. ThereNo.1023,Shatai are three Nan members Road, Guangzhou of the (China); pancreatic Tel.+8613825199222, polypeptide +8618902309513, family, E-Mail [email protected], [email protected] Cellular Physiology Cell Physiol Biochem 2018;45:88-107 DOI: 10.1159/000486225 © 2018 The Author(s). Published by S. Karger AG, Basel and Biochemistry Published online: January 08, 2018 www.karger.com/cpb 89 Yi et al.: NPY Receptors in Metabolic Diseases - namely the neuropeptide Y, the gut-derived hormone peptide YY (PYY) and pancreatic poly- peptide (PP). Endogenous ligands (usually NPY, PYY and PP) and their C-terminal segments, monomerespecially proteinsthose with and parent belong residues to the class 3-36 A and or rhodopsin-like 13-36 [2, 3] activate G-protein Y receptors coupled receptorsvia bind ing and triggering a conformational change of the Y0 receptors (Table 1). NPY receptors are (GPCRs) [4]. After binding to the ligands, the Gi or G subunit of the heterotrimeric G protein- complex is released2+ and and K in+ turn leads to the inhibition of adenylate cyclase, which prevents tothe the conversion Gi or G0 of ATP to the second signaling molecule, cAMP [4]. Finally, cAMP levels are re duced and the Ca channels are modulated [5]. Generally, NPY receptors are coupled- subunit. In rabbit smooth muscle cells, it has also been reported that Y2 and Y4- receptors could bind to the Gq protein and+ promote2+ the production of inositol 1, 4,5-triphos phate (IP3) by activating phospholipase C-β (PLC) [6]. In rat arcuate neurons, it was report- ed that NPY receptors could regulate K and Ca channels, and G protein-coupled inwardly Tablerectifying 1. potassium channels (Fig. 1) [4]. In addition to the seven membrane-confined he The Characteristics of NPY Receptors In Humans The characteristics of NPY receptors in humans NPY receptor Y1 [140] NPY receptor Y2 [141] NPY receptor Y4 [142] NPY receptor Y5 [143] Amino acids 384 381 375 445-455 Expression Periphery, Brain, hippocampus, thalamus, Brain, gastrointestinal tract, Hypothalamus, hippocampus hypothalamus, hypothalamus pancreas, prostate hippocampus, neocortex, thalamus Sequence of pNPY YPSKPDNPGEDAPAEDLARYYSALRHYINLITRQRY ligand hPYY YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY structure hPP APLEPVYPGDNATPEQMAQYAADLRRYINMLTRPRY Agonists NPY (endogenous NPY (endogenous agonist); NPY PP; NPY (endogenous agonist, NPY (endogenous agonist); agonist, non-subtype fragment 13-36(selective); 2- non-subtype selective); PYY; BWX-46 (selective NPY5 selective); PYY Thiouridine 5'triphosphate; PYY; PYY 3- GR-231,118 (mixed NPY1 agonist); PYY 36 fragment antagonist / NPY4 agonist) Antagonists 1.Peptide: BVD-10 BIIE-0246 [5, 37, 144, 145], JNJ UR-AK49 CGP-71683, FMS-586 [6],L- (selective NPY1 5207787 ,SF 11 152,804,Lu AA-33810 [7],MK- antagonist), GR-231,118 0557 [8], NTNCB [9], (mixed NPY1 antagonist Velneperit / NPY4 agonist) 2.Non-peptide: BIBO- 3304,BIBP-3226,PD- 160,170 Location Chr 4: 163.32 – 163.34 Chr 4: 155.21 – 155.22 Mb Chr 10: 46.46 – 46.47 Mb Chr 4: 163.34 – 163.35 Mb Mb Function vasoconstriction, Memory, circadian rhythm, Feeding, circadian ingestion, Food intake, epilepsy, circadian anxiolysis, food intake, angiogenesis, epilepsy, secretion, bone energy homeostasis, colonic rhythm heart rate, anxiety formation transit Molecular NPY receptor /GPCR/Signal transduction function protein binding; PYY/ protein binding; PYY/PP receptor PP receptor PYY/PP receptor PP receptor calcium channel regulation Biological GPCR/AC-inhibiting GPCR/cell surface receptor /AC- GPCR/cell surface GPCR/cell surface receptor/ process GPCR/cell surface inhibiting GPCR/dopamine secretion/ receptor/neuropeptide neuropeptide signaling receptor/ neuropeptide neuropeptide signaling pathways signaling pathways pathway signaling pathways positive regulation of cytosolic calcium blood circulation positive regulation of acute locomotory behavior ion concentration/peptide secretion feeding behavior inflammatory response/cell regulation of and circadian sleep/wake cycle, non- digestion and smooth muscle multicellular organism REM sleep/ smooth muscle contraction/ proliferation/ERK1 and ERK2 growth/blood pressure cell-substrate adhesion cascade outflow tract negative regulation of neurological negative regulation of morphogenesis system process/synaptic glutamate secretion/apoptotic blood circulation transmission/excitatory postsynaptic process/synaptic transmission, feeding behavior potential/ secretion/ feeding GABAergic/acute inflammatory glucose metabolic behavior/cAMP biosynthetic response to antigenic stimulus process process/synaptic transmission, generation of ovulation cycle sensory perception of glutamatergic rhythm pain sensory perception of pain eating/feeding behavior locomotory/feeding behavior outflow tract morphogenesis outflow tract morphogenesis aging cardiac left ventricle morphogenesis cardiac left ventricle behavioral fear response morphogenesis nitric oxide mediated signal chemical synaptic transmission transduction aging chemical synaptic transmission Cellular Physiology Cell Physiol Biochem 2018;45:88-107 DOI: 10.1159/000486225 © 2018 The Author(s). Published by S. Karger AG, Basel and Biochemistry Published online: January 08, 2018 www.karger.com/cpb 90 Yi et al.: NPY Receptors in Metabolic Diseases lices, the heptahelical GPCRs have four extracellular and four intracellular segments, which- could be labeled as ec1-ec4 and ic1-ic4, respectively. The ec1 is an extracellular N-terminus and the ic4 is a intracellular C-terminus which cloud anchor onto the membrane by palmi toylation. The other six segments form three extracellular loops I-III and intracellular loops I-III was formed by the ec2-ec4 and ic1-ic3 segments, respectively. In extracellular regions, a disulfide bond between ec2 and ec3 segments is formed by two highly conserved cysteine (Cys) residues. This disulfide bond is a general feature of class A GPCRs and has been related to the stability of these receptors [7, 8]. The extracellular parts of the receptor can also be modified by glycosylation. In the intracellular regions, the C terminal tail, namely the ic4 ansegment, elementary and the complex ic2 segment coupled form to Y tworeceptors G protein [9]. binding sites. These two helices interact with signal transduction protein GTPases and bind to G proteins which consequently form Thus far, seven different Y receptors (Y1-Y8) have been
Load more

Recommended publications
  • Neuropeptide Y6 Receptors Are Critical Regulators of Energy Metabolism
    NEUROPEPTIDE Y6 RECEPTORS ARE CRITICAL REGULATORS OF ENERGY METABOLISM Ernie Yulyaningsih A thesis in fulfilment of the requirements for the degree of Doctor of Philosophy St Vincent’s Clinical School Faculty of Medicine February 2014 Table of Contents GENERAL INTRODUCTION ....................................................................... 2 Obesity .......................................................................................................... 3 Regulators of energy homeostasis................................................................ 3 Neuropeptide Y ............................................................................................ 4 The Y1 receptor ......................................................................................... 6 The Y2 receptor ......................................................................................... 9 The Y4 receptor ....................................................................................... 16 The Y5 receptor ....................................................................................... 21 The Y6 receptor ....................................................................................... 25 Hypothesis and overall aims of the study .................................................. 28 EXPERIMENTAL PROCEDURES ............................................................. 29 Generation and genotyping of the Y6-/--LacZ mouse ................................ 30 Animal experiments ..................................................................................
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2012/0022039 A1 Schwink Et Al
    US 20120022039A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0022039 A1 Schwink et al. (43) Pub. Date: Jan. 26, 2012 (54) NOVEL SUBSTITUTED INDANES, METHOD Publication Classification FOR THE PRODUCTION THEREOF, AND USE (51) Int. Cl. THEREOF AS DRUGS A 6LX 3L/397 (2006.01) C07D 207/06 (2006.01) C07D 2L/22 (2006.01) C07D 22.3/04 (2006.01) (75) Inventors: Lothar Schwink, Frankfurt am C07D 22L/22 (2006.01) Main (DE); Siegfried Stengelin, C07C 235/54 (2006.01) Frankfurt am Main (DE); Matthias C07D 307/14 (2006.01) Gossel, Frankfurt am Main (DE); A63L/35 (2006.01) Klaus Wirth, Frankfurt am Main A6II 3/40 (2006.01) (DE) A6II 3/445 (2006.01) A6II 3/55 (2006.01) A63L/439 (2006.01) A6II 3/66 (2006.01) (73) Assignee: SANOFI, Paris (FR) A6II 3/34 (2006.01) A6IP3/10 (2006.01) A6IP3/04 (2006.01) A6IP3/06 (2006.01) (21) Appl. No.: 13/201410 A6IPL/I6 (2006.01) A6IP3/00 (2006.01) C07D 309/04 (2006.01) (52) U.S. Cl. .................... 514/210.01; 549/426: 548/578; (22) PCT Filed: Feb. 12, 2010 546/205; 540/484; 546/112:564/176; 549/494; 514/459:514/408: 514/319; 514/212.01; 514/299; 514/622:514/471 (86). PCT No.: PCT/EP2010/051796 (57) ABSTRACT The invention relates to substituted indanes and derivatives S371 (c)(1), thereof, to physiologically acceptable salts and physiologi (2), (4) Date: Oct. 4, 2011 cally functional derivatives thereof, to the production thereof, to drugs containing at least one substituted indane according (30) Foreign Application Priority Data to the invention or derivative thereof, and to the use of the Substituted indanes according to the invention and to deriva Feb.
    [Show full text]
  • Stems for Nonproprietary Drug Names
    USAN STEM LIST STEM DEFINITION EXAMPLES -abine (see -arabine, -citabine) -ac anti-inflammatory agents (acetic acid derivatives) bromfenac dexpemedolac -acetam (see -racetam) -adol or analgesics (mixed opiate receptor agonists/ tazadolene -adol- antagonists) spiradolene levonantradol -adox antibacterials (quinoline dioxide derivatives) carbadox -afenone antiarrhythmics (propafenone derivatives) alprafenone diprafenonex -afil PDE5 inhibitors tadalafil -aj- antiarrhythmics (ajmaline derivatives) lorajmine -aldrate antacid aluminum salts magaldrate -algron alpha1 - and alpha2 - adrenoreceptor agonists dabuzalgron -alol combined alpha and beta blockers labetalol medroxalol -amidis antimyloidotics tafamidis -amivir (see -vir) -ampa ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) subgroup: -ampanel antagonists becampanel -ampator modulators forampator -anib angiogenesis inhibitors pegaptanib cediranib 1 subgroup: -siranib siRNA bevasiranib -andr- androgens nandrolone -anserin serotonin 5-HT2 receptor antagonists altanserin tropanserin adatanserin -antel anthelmintics (undefined group) carbantel subgroup: -quantel 2-deoxoparaherquamide A derivatives derquantel -antrone antineoplastics; anthraquinone derivatives pixantrone -apsel P-selectin antagonists torapsel -arabine antineoplastics (arabinofuranosyl derivatives) fazarabine fludarabine aril-, -aril, -aril- antiviral (arildone derivatives) pleconaril arildone fosarilate -arit antirheumatics (lobenzarit type) lobenzarit clobuzarit -arol anticoagulants (dicumarol type) dicumarol
    [Show full text]
  • Instituto Superior De Ciências Da Saúde Egas Moniz
    INSTITUTO SUPERIOR DE CIÊNCIAS DA SAÚDE EGAS MONIZ MESTRADO INTEGRADO EM CIÊNCIAS FARMACÊUTICAS REGULAÇÃO DO COMPORTAMENTO ALIMENTAR E NOVOS ALVOS TERAPÊUTICOS Trabalho submetido por Christelle Sophia Paulino Rodrigues para a obtenção do grau de Mestre em Ciências Farmacêuticas Trabalho orientado por Doutora Véronique Sena Outubro de 2013 Agradecimentos Agradecimentos Embora esta tese seja individual, não poderia deixar de usar este espaço para agradecer quem me apoiou durante esta fase e durante os cinco anos anteriores aquando a minha formação académica. As palavras não são suficientes para descrever o sentimento de agradecimento, mas o sentimento é real e profundo. Em primeiro lugar, gostaria de agradecer o Instituto Superior de Ciências da Saúde Egas Moniz que me forneceu o ensino adequado para me ajudar a cumprir os meus objetivos. À professora Véronique pela presença, pela orientação, pelo tempo de dedicou e pela ajuda que forneceu. Este trabalho não teria existido sem a professora. À Salete e ao Francisco que se disponibilizaram para me ajudar a corrigir a gramática e a ortografia. Ao meus amigos, familiares e colegas, que sempre acreditaram em mim. Ao meu irmão, por ser quem é. Aos meus pais pelo apoio moral, pela dedicação, pelo carinho e pelos sacrifícios que fizeram para eu chegar ao fim desta etapa. Dedico-lhes esta tese por isso, e por tudo o mais que fizeram por mim. A todos, obrigado. 3 Regulação do comportamento alimentar e novo alvos terapêuticos Resumo O comportamento alimentar depende da regulação do equilíbrio entre a ingestão de calorias e o gasto energético. Esta regulação ocorre a nível cerebral onde o hipotálamo exerce um papel fundamental.
    [Show full text]
  • GPCR/G Protein
    Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33.
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Velneperit Item No. 33850 CAS Registry No.: 342577-38-2 Formal Name: trans-4-[[(1,1-dimethylethyl)sulfonyl] F amino]-N-[5-(trifluoromethyl)-2-pyridinyl]- F cyclohexanecarboxamide N F Synonym: S-2367 O MF: C17H24F3N3O3S FW: 407.5 O N Purity: ≥98% S H UV/Vis.: λ: 244, 279 nm N max O Supplied as: A solid H Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Velneperit is supplied as a solid. A stock solution may be made by dissolving the velneperit in the solvent of choice, which should be purged with an inert gas. Velneperit is soluble in the organic solvent DMSO. Description 1 Velneperit is a nonpeptide antagonist of neuropeptide Y (NPY) receptor Y5 (Ki = 5.3 nM). It is selective for Y5 over Y1, Y2, and Y4 receptors, as well as a panel of 44 receptors, ion channels, transporters and enzymes, at 10 µM. Velneperit inhibits NPY-induced decreases in forskolin-induced cAMP production in CHO-K1 cells expressing the human Y5 receptor (IC50 = 169 nM). In vivo, velneperit (50 mg/kg) suppresses Y5 agonist-induced increases in food intake in high-fat diet-induced obese (DIO) mice. It also reduces body weight gain and suppresses food intake in DIO mice. Reference 1. Fukasaka, Y., Nambu, H., Tanioka, H., et al. An insurmountable NPY Y5 receptor antagonist exhibits superior anti-obesity effects in high-fat diet-induced obese mice. Neuropeptides 70, 55-63 (2018). WARNING CAYMAN CHEMICAL THIS PRODUCT IS FOR RESEARCH ONLY - NOT FOR HUMAN OR VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau Et Al
    US 20150202317A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau et al. (43) Pub. Date: Jul. 23, 2015 (54) DIPEPTDE-BASED PRODRUG LINKERS Publication Classification FOR ALPHATIC AMNE-CONTAINING DRUGS (51) Int. Cl. A647/48 (2006.01) (71) Applicant: Ascendis Pharma A/S, Hellerup (DK) A638/26 (2006.01) A6M5/9 (2006.01) (72) Inventors: Harald Rau, Heidelberg (DE); Torben A 6LX3/553 (2006.01) Le?mann, Neustadt an der Weinstrasse (52) U.S. Cl. (DE) CPC ......... A61K 47/48338 (2013.01); A61 K3I/553 (2013.01); A61 K38/26 (2013.01); A61 K (21) Appl. No.: 14/674,928 47/48215 (2013.01); A61M 5/19 (2013.01) (22) Filed: Mar. 31, 2015 (57) ABSTRACT The present invention relates to a prodrug or a pharmaceuti Related U.S. Application Data cally acceptable salt thereof, comprising a drug linker conju (63) Continuation of application No. 13/574,092, filed on gate D-L, wherein D being a biologically active moiety con Oct. 15, 2012, filed as application No. PCT/EP2011/ taining an aliphatic amine group is conjugated to one or more 050821 on Jan. 21, 2011. polymeric carriers via dipeptide-containing linkers L. Such carrier-linked prodrugs achieve drug releases with therapeu (30) Foreign Application Priority Data tically useful half-lives. The invention also relates to pharma ceutical compositions comprising said prodrugs and their use Jan. 22, 2010 (EP) ................................ 10 151564.1 as medicaments. US 2015/0202317 A1 Jul. 23, 2015 DIPEPTDE-BASED PRODRUG LINKERS 0007 Alternatively, the drugs may be conjugated to a car FOR ALPHATIC AMNE-CONTAINING rier through permanent covalent bonds.
    [Show full text]
  • Orally Active Compound Library (96-Well)
    • Bioactive Molecules • Building Blocks • Intermediates www.ChemScene.com Orally Active Compound Library (96-well) Product Details: Catalog Number: CS-L061 Formulation: A collection of 2244 orally active compounds supplied as pre-dissolved Solutions or Solid Container: 96- or 384-well Plate with Peelable Foil Seal; 96-well Format Sample Storage Tube With Screw Cap and Optional 2D Barcode Storage: -80°C Shipping: Blue ice Packaging: Inert gas Plate layout: CS-L061-1 1 2 3 4 5 6 7 8 9 10 11 12 a Empty Vonoprazan Mivebresib AZD0156 BAY-876 Tomivosertib PQR620 NPS-2143 R547 PAP-1 Delpazolid Empty Varenicline b Empty Varenicline (Hydrochlorid Varenicline A-205804 CI-1044 KW-8232 GSK583 Quiflapon MRK-016 Diroximel Empty e) (Tartrate) fumarate SHP099 c Empty A 922500 SHP099 (hydrochlorid Nevanimibe Pactimibe Pactimibe GNF-6231 MLi-2 KDM5-IN-1 PACMA 31 Empty e) hydrochloride (sulfate) Rilmenidine d Empty Cadazolid Treprostinil GSK3179106 Esaxerenone (hemifumarat Rilmenidine Fisogatinib BP-1-102 Avadomide Aprepitant Empty e) (phosphate) Cl-amidine AZD5153 (6- e Empty Maropitant Abscisic acid (hydrochlorid BGG463 WNK463 Ticagrelor Axitinib Hydroxy-2- CGS 15943 Pipamperone Empty e) naphthoic Setogepram Teglarinad f Empty Y-27632 GSK2193874 Lanabecestat CXD101 Ritlecitinib YL0919 PCC0208009 (sodium salt) (chloride) Futibatinib Empty TAK-659 g Empty NCB-0846 GS-444217 (hydrochlorid Navitoclax ABX464 Zibotentan Simurosertib (R)- CEP-40783 MK-8617 Empty e) Simurosertib Choline JNJ- h Empty CCT251236 (bitartrate) Sarcosine Brensocatib AS-605240 PF-06840003
    [Show full text]
  • Antiobesity Pharmacotherapy: New Drugs and Emerging Targets
    State of the Art nature publishing group STATE ART Antiobesity Pharmacotherapy: New Drugs and Emerging Targets GW Kim1, JE Lin1, ES Blomain1 and SA Waldman1 Obesity is a growing pandemic, and related health and economic costs are staggering. Pharmacotherapy, partnered with lifestyle modifications, forms the core of current strategies to reduce the burden of this disease and its sequelae. However, therapies targeting weight loss have a significant history of safety risks, including cardiovascular and psychiatric events. Here, evolving strategies for developing antiobesity therapies, including targets, mechanisms, and developmental status, are highlighted. Progress in this field is underscored by Belviq (lorcaserin) and Qsymia (phentermine/topiramate), the first agents in more than 10 years to achieve regulatory approval for chronic weight management in obese patients. On the horizon, novel insights into metabolism and energy homeostasis reveal guanosine 3′,5′-cyclic monophosphate (cGMP) signaling circuits as emerging targets for antiobesity pharmacotherapy. These innovations in molecular discovery may elegantly align with practical off-the-shelf approaches, leveraging existing approved drugs that modulate cGMP levels for the management of obesity. Obesity is a global public health problem. The obesity epidemic prepared foods vs. fast foods or prepackaged foods in terms has been growing in developed nations, including the United of preservation, portability, and palatability; the marketing of States, for decades.1 Moreover, this epidemic
    [Show full text]
  • A Abacavir Abacavirum Abakaviiri Abagovomab Abagovomabum
    A abacavir abacavirum abakaviiri abagovomab abagovomabum abagovomabi abamectin abamectinum abamektiini abametapir abametapirum abametapiiri abanoquil abanoquilum abanokiili abaperidone abaperidonum abaperidoni abarelix abarelixum abareliksi abatacept abataceptum abatasepti abciximab abciximabum absiksimabi abecarnil abecarnilum abekarniili abediterol abediterolum abediteroli abetimus abetimusum abetimuusi abexinostat abexinostatum abeksinostaatti abicipar pegol abiciparum pegolum abisipaaripegoli abiraterone abirateronum abirateroni abitesartan abitesartanum abitesartaani ablukast ablukastum ablukasti abrilumab abrilumabum abrilumabi abrineurin abrineurinum abrineuriini abunidazol abunidazolum abunidatsoli acadesine acadesinum akadesiini acamprosate acamprosatum akamprosaatti acarbose acarbosum akarboosi acebrochol acebrocholum asebrokoli aceburic acid acidum aceburicum asebuurihappo acebutolol acebutololum asebutololi acecainide acecainidum asekainidi acecarbromal acecarbromalum asekarbromaali aceclidine aceclidinum aseklidiini aceclofenac aceclofenacum aseklofenaakki acedapsone acedapsonum asedapsoni acediasulfone sodium acediasulfonum natricum asediasulfoninatrium acefluranol acefluranolum asefluranoli acefurtiamine acefurtiaminum asefurtiamiini acefylline clofibrol acefyllinum clofibrolum asefylliiniklofibroli acefylline piperazine acefyllinum piperazinum asefylliinipiperatsiini aceglatone aceglatonum aseglatoni aceglutamide aceglutamidum aseglutamidi acemannan acemannanum asemannaani acemetacin acemetacinum asemetasiini aceneuramic
    [Show full text]
  • NPY Receptors As Potential Targets for Anti-‐Obesity Drug Development
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Sydney eScholarship Yulyaningsih et al.: Anti-obesity drug development British Journal of Pharmacology, 163(6): 1170-1202 NPY receptors as potential targets for anti-obesity drug development Ernie Yulyaningsih1, Lei Zhang1, Herbert Herzog1,2 and Amanda Sainsbury1,3 1 Neuroscience Research Program, Garvan Institute of Medical Research, St Vincent’s Hospital, Darlinghurst, Sydney, NSW, 2 3 Australia, Faculty of Medicine, University of NSW, Sydney, NSW, Australia, and School of Medical Sciences, University of NSW, Sydney, NSW, Australia Abstract The neuropeptide Y system has proven to be one of the most important regulators of feeding behaviour and energy homeostasis, thus presenting great potential as a therapeutic target for the treatment of disorders such as obesity and at the other extreme, anorexia. Due to the initial lack of pharmacological tools that are active in vivo, functions of the different Y receptors have been mainly studied in knockout and transgenic mouse models. However, over recent years various Y receptor selective peptidic and non-peptidic agonists and antagonists have been developed and tested. Their therapeutic potential in relation to treating obesity and other disorders of energy homeostasis is discussed in this review. Abbreviations ARC, arcuate nucleus; d.d., dose-dependent; i.c.v., intracerebroventricular; i.p., intraperitoneal; NPY, neuropeptide Y; p.o., per oral; PP, pancreatic polypeptide; PVN, paraventricular nucleus; PYY, polypeptide YY Introduction One of the most potent inducers of feeding in mammals is neuropeptide Y (NPY), a 36 amino acid neurotransmitter. NPY is part of a family of structurally related peptides that also includes the hormones polypeptide YY (PYY) and pancreatic polypeptide (PP).
    [Show full text]
  • To Investigate the Physiological Role of Arcuate Nucleus Cocaine- and Amphetamine- Regulated Transcript in Energy Homeostasis
    To Investigate the Physiological Role of Arcuate Nucleus Cocaine- and Amphetamine- Regulated Transcript in Energy Homeostasis. Thesis submitted for the degree of Doctor of Philosophy in Imperial College London Daniel Charles Campbell 2010 Department of Investigative Medicine Faculty of Medicine Imperial College London 1 For my mum and dad, brothers and sisters 2 Abstract Cocaine- and amphetamine- regulated transcript (CART) was originally identified as a mRNA transcript upregulated in rats in response to administration of cocaine and amphetamine. CART is widely expressed in the central nervous system (CNS) with high levels of expression in hypothalamic nuclei such as the arcuate nucleus (ARC). CART was initially thought to act as an anorectic peptide since it is coexpressed with the anorectic neuropeptide pro-opiomelanocortin (POMC) in the ARC. In addition, intracerebroventricular (ICV) administration of CART (55-102) peptide inhibits feeding and administration of anti-CART antibody results in stimulation of feeding. However, subsequent studies have suggested CART may also act as an orexigen since injection of CART (55-102) specifically into the ARC and ventromedial nucleus (VMN) of the hypothalamus results in a significant increase in food intake. These data suggest CART acts through both anorectic and orexigenic circuits. Given the importance of the hypothalamus in the regulation of energy homeostasis, and the role of the ARC in integrating peripheral signals, it is essential to elucidate the role of ARC derived CART. In order to elucidate CART’s true physiological role in the ARC I used a combination of genetic approaches. I generated a recombinant Adeno-associated virus (rAAV) expressing CART antisense (CART-AS) and a transgenic mouse model which utilises the POMC promoter to drive expression of CART-AS.
    [Show full text]