DOCSLIB.ORG

Identification of the Receptor Subtype Involved in the Analgesic Effect Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification of the Receptor Subtype Involved in the Analgesic Effect Of The Journal of Neuroscience, January 1, 1999, 19(1):503–510 Identification of the Receptor Subtype Involved in the Analgesic Effect of Neurotensin Isabelle Dubuc,1 Philippe Sarret,2 Catherine Labbe´ -Jullie´,2 Jean-Marie Botto,2 Eric Honore´,2 Elisabeth Bourdel,3 Jean Martinez,3 Jean Costentin,1 Jean-Pierre Vincent,2 Patrick Kitabgi,2 and Jean Mazella2 1Unite´ de Neuropsychopharmacologie Expe´ rimentale, Centre National de la Recherche Scientifique (CNRS), 76803 Saint Etienne du Rouvray, France, 2Institut de Pharmacologie Mole´ culaire et Cellulaire, CNRS, 06560 Valbonne, France, and 3Laboratoire des Aminoacides, Peptides et Prote´ ines, ESA CNRS, Faculte´ de Pharmacie, Universite´ s de Montpellier 1 et 2, 34060 Montpellier, France. The neuropeptide neurotensin (NT) elicits hypothermic and This effect was specific, because NTR1 levels were unaffected, naloxone-insensitive analgesic responses after brain injection. and sense or scramble oligodeoxynucleotides had no effect. Recent pharmacological evidence obtained with NT agonists Structure–activity studies revealed a close correlation between and antagonists suggests that these effects are mediated by a the analgesic potency of NT analogs and their affinity for the receptor distinct from the initially cloned high-affinity NT recep- NTR2 and disclosed potent and selective agonists of this re- tor (NTR1). The recent cloning of a second NT receptor (NTR2) ceptor. These data confirm that NTR1 is involved in the NT- prompted us to evaluate its role in NT-induced analgesia. Intra- elicited turning behavior and demonstrate that the NTR2 me- cerebroventricular injections in mice of two different antisense diates NT-induced analgesia. oligodeoxynucleotides from the NTR2 markedly decreased Key words: analgesia; neurotensin; receptor; levocabastine- NTR2 mRNA and protein and reduced NT-induced analgesia. sensitive; oligodeoxynucleotide; antisense The neuropeptide neurotensin (NT) exerts important central not correlate with their binding affinity for the NTR1 (Labbe´- functions, including hypothermic and naloxone-insensitive anal- Jullie´ et al., 1994). gesic responses after brain injection (Al-Rhodan et al., 1991; for To investigate a possible role of the NTR2 in mediating NT- review, see Vincent, 1995). NT interacts with two recently cloned induced hypothermia and analgesia, we attempted to selectively receptors that were originally differentiated on the basis of their block its central expression using in vivo antisense strategies (for affinity for NT and their sensitivity to the antihistaminic drug review, see Akhtar and Agrawal, 1997). The amount of levocabastine (Schotte et al., 1986). The high-affinity, levocabastine-sensitive NT binding sites and the resulting re- levocabastine-insensitive NT receptor (NTR1) was cloned first sponses to NT-induced analgesia were specifically decreased in (Tanaka et al., 1990; Vita et al., 1993) and shown to mediate a mice intracerebroventricularly injected with specific NTR2 anti- number of peripheral and central NT responses, including the sense oligodeoxynucleotides (ODNs) compared with control an- neuroleptic-like effects of the peptide (Labbe´-Jullie´ et al., 1994). imals injected with solvent, NTR2 sense and scramble ODNs, or In contrast, the functional relevance of the lower-affinity, with antisense NTR1 ODNs. These results, added to structure– levocabastine-sensitive NT receptor (NTR2) cloned later (Cha- activity studies, identify NTR2 as the receptor that mediates lon et al., 1996; Mazella et al., 1996) remains to be established. NT-induced analgesia. Pharmacological evidence suggested that two of the most prom- inent effects of centrally injected NT i.e., analgesia (Clineschmidt MATERIALS AND METHODS et al., 1979; Nemeroff et al., 1979; Martin and Naruse, 1982; ODN administration. A first pair of sense and antisense oligodeoxynucle- Behbehani and Pert, 1984; Coquerel et al., 1988) and hypother- otides (ODN1) was chosen to span the translation start site of the mouse NTR2 (Mazella et al., 1996). Their sequences are as follows: sense, mia (Bissette et al., 1976), were not mediated by the NTR1. Thus, 59-ATG-GAG-ACC-AGC-AGC-CTG-39; and antisense, 59-CAG-GCT- the recently developed nonpeptide NT antagonist SR 48692 (Gul- GCT-GGT-CTC-CAT-39. A second pair of phosphorothioate antisense ly et al., 1993), which preferentially recognizes the NTR1, did not and scramble ODN2 corresponded to nucleotides 30–47 in the coding antagonize these effects (Dubuc et al., 1994). Furthermore, a sequence of NTR2: antisense, 59-CCT-GCA-CTG-GGG-CTG-GGC-39; 9 9 number of metabolically stable peptide and pseudopeptide NT and scramble, 5 -CTC-TCC-GAG-CGG-GTG-GCG-3 . We also synthe- sized phosphorothioate ODNs spanning the translation start site of the analogs exhibited analgesic and hypothermic potencies that did rat NTR1 (Tanaka et al., 1990): antisense, 59-GGA-GCT-GTT-GAG- GTG-CAT-39; and scramble, 59-GAG-GTC-TTG-GAG-TGG-ACT-39. All these ODNs, synthesized by Eurogentec and analyzed by OLIGO 4.0 Received July 7, 1998; revised Oct. 15, 1998; accepted Oct. 22, 1998. (National Biosciences, Inc.), were devoid of internal hair loops and putative cross-reactions. In preliminary experiments with ODN1, mice We thank G. Jarretou and M. Jodar for technical assistance and F. Aguila for photographic work. A special thanks is given to Dr. A. Beaudet for carefully reading were treated with either a single ODN injection per day for4dorwith this manuscript. two ODN injections per day for 3 d, and behavioral tests were performed Correspondence should be addressed to Jean Mazella, Institut de Pharmacologie on the fifth day. There was no change in the hypothermic and analgesic Mole´culaire et Cellulaire, Centre National de la Recherche Scientifique, Unite´ responses to NT in antisense ODN-treated animals compared with Propre de Recherche 411, 660 Route des Lucioles, 06560 Valbonne, France. control animals. The working conditions then selected for ODN1 were Copyright © 1998 Society for Neuroscience 0270-6474/98/190503-08$05.00/0 two intracerebroventricular injections (9:00 A.M. and 6:00 P.M.) for 4 504 J. Neurosci., January 1, 1999, 19(1):503–510 Dubuc et al. • Neurotensin Receptors and Analgesia 125 3 125 3 Figure 1. I-Tyr -NT binding to homogenates of CHO cells or mouse brains treated with solvent or ODNs. A, Densities (Bmax )of I-Tyr -NT binding to membranes from NTR2-expressing CHO cells treated for3dwithsolvent (Svt), sense (S), scramble (Scr), or antisense (AS) ODN1 NTR2 6 or ODN2 NTR2. Results are expressed as percentage of Bmax values obtained from cells treated with DAC-30 alone (Svt): 290 25 fmol/mg protein 5 (n 4). B, C, Densities (Bmax ) of levocabastine-insensitive (NTR1) and levocabastine-sensitive (NTR2) NT receptors in mouse brain homogenates treated with ODN1 NTR2 (B) or ODN2 NTR2 (C). The total and NTR1-specific amount of NT binding sites determined in solvent (Svt), sense (S), or scramble (Scr) ODN-treated mice were similar to those reported previously in mouse brain (Mazella et al., 1988). Bmax values were extrapolated from saturation curves fitted with the LIGAND program. Values are mean 6 SEM from two (A) and three (B, C) independent experiments. Data were tested for significance with a Student’s t test; *p , 0.01 compared with solvent-injected mice. consecutive days, followed by behavioral tests on the fifth day. of DAC-30 was unable to decrease the amount of bound iodinated NT to When unprotected ODN2 (scramble or antisense) was injected according membranes from CHO cells expressing the NTR2. to the latter protocol, no effect on NT-induced responses was observed. Transfection of cDNA encoding the mNTR2 and binding experiments. It was checked in this case that ODN treatment did not modify the The eukaryotic expression vector (pcDNA3) containing the 1.6 kb binding of NT to either NTR1 or NTR2. The use of phosphorothioate EcoRI-ApaI fragment of the NTR2 cDNA was used to transiently trans- ODN2 (scramble and antisense) following the same protocol showed fect COS-7 cells by the DEAE–dextran precipitation method (Cullen, some toxicity in the treated mice. The final selected conditions for 1987). Stable expression of the NTR2 into CHO cells was obtained by phosphorothioate ODN2 treatment were two intracerebroventricular transfection with 5 mg of recombinant pcDNA3 vector using 25 mgofthe injections per day for 3 consecutive days, followed by behavioral tests on cationic liposome DAC-30 (Eurogentec) according to the manufacturer’s the fourth day. recommendations. Clonal cell lines were selected by Geneticin (Sigma) Measurements of biological effects. All drugs were intracerebroventricu- (0.5 mg/ml) and isolated before determination of expression level. The larly injected in male Swiss CD1 mice (22–24 gm; Charles River, Saint- clonal cell line expressing the highest level of NTR2 was selected and Aubin-le`s Elbeuf, France) according to the method of Haley and Mc used for in vitro experiments. Cormick (1957). All ODNs were injected at 10 ml at a dose of 20 mg (3.6 Binding experiments were performed as described previously (Ma- nmol). All experimental groups of mice consisted of 10–12 animals. On zella et al., 1996) using either membranes prepared from brains treated the test day, NT (10 ng 5 6.7 pmols or 100 ng 5 67 pmols) or solvent (7% with solvent or ODNs, or homogenates freshly prepared from cells saline, 10 ml) was intracerebroventricularly injected. Colonic tempera- transiently (COS-7) or stably (CHO) transfected with the NTR2. Spinal ture was measured with a thermistor probe (Thermalert TH5; Physitemp, cord was not analyzed, because this organ primarily contains the inactive Clifton, NJ) introduced at a depth of 2 cm into the rectum, immediately variant of NTR2 (Botto et al., 1997b) and because NT analgesic effects before and 20 min after the intracerebroventricular injection. Antinoci- are known to be of supraspinal origin (Martin and Naruse, 1982). ception was determined by the writhing test according to Koster et al. Homogenates, 50 mg of protein from treated cells or 100 mg of protein (1959).
Load more

Recommended publications
  • LGM-Pharma-Regulatory-1527671011
    Pipeline Products List Specialty Portfolio Updated Q2 2018 Updated Q2 2018 See below list of newly approved API’s, samples are readily available for your R&D requirements: Inhalation Ophthalmic Transdermal Sublingual Abaloparatide Defibrotide Sodium Liraglutide Rituximab Abciximab Deforolimus Lixisenatide Rivastigmine Aclidinium Bromide Azelastine HCl Agomelatine Alprazolam Abemaciclib Delafloxacin Lumacaftor Rivastigmine Hydrogen Tartrate Beclomethasone Dipropionate Azithromycin Amlodipine Aripiprazole Acalabrutinib Denosumab Matuzumab Rizatriptan Benzoate Budesonide Besifloxacin HCl Apomorphine Eletriptan HBr Aclidinium Bromide Desmopressin Acetate Meloxicam Rocuronium Bromide Adalimumab Difluprednate Memantine Hydrochloride Rolapitant Flunisolide Bimatoprost Clonidine Epinephrine Aflibercept Dinoprost Tromethamine Micafungin Romidepsin Fluticasone Furoate Brimonidine Tartrate Dextromethorphan Ergotamine Tartrate Agomelatine Dolasetron Mesylate Mitomycin C Romosozumab Fluticasone Propionate Bromfenac Sodium Diclofenac Levocetrizine DiHCl Albiglutide Donepezil Hydrochloride Mometasone Furoate Rotigotine Formoterol Fumarate Cyclosporine Donepezil Meclizine Alectinib Dorzolamide Hydrochloride Montelukast Sodium Rucaparib Iloprost Dexamethasone Valerate Estradiol Melatonin Alemtuzumab Doxercalciferol Moxifloxacin Hydrochloride Sacubitril Alirocumab Doxorubicin Hydrochloride Mycophenolate Mofetil Salmeterol Xinafoate Indacaterol Maleate Difluprednate Fingolimod Meloxicam Amphotericin B Dulaglutide Naldemedine Secukinumab Levalbuterol Dorzolamide
    [Show full text]
  • Regulation of Ventral Tegmental Area Dopamine Neuron Activity by Feeding-Related Hypothalamic Neuropeptides
    Georgia State University ScholarWorks @ Georgia State University Neuroscience Institute Dissertations Neuroscience Institute 8-7-2018 Regulation of Ventral Tegmental Area Dopamine Neuron Activity by Feeding-related Hypothalamic Neuropeptides Katherine MS West Georgia State University Follow this and additional works at: https://scholarworks.gsu.edu/neurosci_diss Recommended Citation West, Katherine MS, "Regulation of Ventral Tegmental Area Dopamine Neuron Activity by Feeding-related Hypothalamic Neuropeptides." Dissertation, Georgia State University, 2018. https://scholarworks.gsu.edu/neurosci_diss/36 This Dissertation is brought to you for free and open access by the Neuroscience Institute at ScholarWorks @ Georgia State University. It has been accepted for inclusion in Neuroscience Institute Dissertations by an authorized administrator of ScholarWorks @ Georgia State University. For more information, please contact [email protected]. REGULATION OF VENTRAL TEGMENTAL AREA DOPAMINE NEURON ACTIVITY BY FEEDING-RELATED HYPOTHALAMIC NEUROPEPTIDES by KATHERINE M. S. WEST Under the Direction of Aaron Roseberry, Ph.D. ABSTRACT The prevalence of obesity has doubled worldwide since the 1980s, and having a high body mass index contributes to more deaths worldwide than being underweight. Over the past 20 years, consumption of calorie-dense foods has increased, and this is considered one of the major causes of the rapid rise in obesity. Thus, understanding the neural control of food intake is important for the development of new and effective treatments of obesity. Two important brain regions that regulate food intake are the hypothalamus and the mesocorticolimbic dopamine system. The hypothalamus is essential for the homeostatic control of feeding and body weight, while the mesocorticolimbic dopamine system, also known as the reward system, is the primary circuit for reward and motivated behavior.
    [Show full text]
  • Report 752 by Category Description
    PAs by Category Description Sorted by Descending Count Date Range: 04/01/2006 through 06/30/2006 Number Number Category of Category of Description PAs Description PAs Cetirizine HCl 792 Ziprasidone HCl 43 Duloxetine HCl 784 Norelgestromin-Ethinyl Estradiol 42 Methylphenidate HCl 646 Nicotine 41 Venlafaxine HCl 620 Levofloxacin 41 Atomoxetine HCl 472 Carisoprodol 41 Quetiapine Fumarate 430 Albuterol 40 Gabapentin 422 Amylase-Lipase-Protease 40 Nutritional Supplements 378 Famotidine 40 Montelukast Sodium 326 Levothyroxine Sodium 39 Zolpidem Tartrate 288 Enoxaparin Sodium 37 Amphetamine-Dextroamphetamine 286 Norgestimate-Ethinyl Estradiol (Triphasic) 37 Aripiprazole 271 Tretinoin 37 Desloratadine 191 Modafinil 36 Fexofenadine HCl 188 Pioglitazone HCl 36 Topiramate 186 Citalopram Hydrobromide 36 Polyethylene Glycol 3350 182 Budesonide (Inhalation) 36 Fentanyl 175 Epoetin Alfa 33 Eszopiclone 174 Etanercept 33 Esomeprazole Magnesium 172 Botulinum Toxin Type A 32 Celecoxib 157 Somatropin 31 Pregabalin 148 Metformin HCl 31 Escitalopram Oxalate 142 Oxycodone w/ Acetaminophen 31 Sertraline HCl 135 Morphine Sulfate 30 Risperidone 127 Levetiracetam 30 Bupropion HCl 118 Clonazepam 30 Tiotropium Bromide Monohydrate 112 Phenobarbital 30 Oxycodone HCl 110 Drospirenone-Ethinyl Estradiol 29 Ezetimibe 105 Rosiglitazone Maleate 29 Clopidogrel Bisulfate 103 Valsartan 29 Ondansetron HCl 97 Memantine HCl 28 Olanzapine 93 Sumatriptan Succinate 28 Temazepam 92 Buprenorphine HCl 28 Oxcarbazepine 82 B-Complex w/ C & Folic Acid 28 Rabeprazole Sodium 74 Ranitidine
    [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]
  • G Protein‐Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology (2019) 176, S21–S141 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors Stephen PH Alexander1 , Arthur Christopoulos2 , Anthony P Davenport3 , Eamonn Kelly4, Alistair Mathie5 , John A Peters6 , Emma L Veale5 ,JaneFArmstrong7 , Elena Faccenda7 ,SimonDHarding7 ,AdamJPawson7 , Joanna L Sharman7 , Christopher Southan7 , Jamie A Davies7 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia 3Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK 4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 5Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 6Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 7Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website.
    [Show full text]
  • Preferred Drug List with Prior Authorization Criteria
    BUREAU FOR MEDICAL SERVICES WEST VIRGINIA MEDICAID PREFERRED DRUG LIST WITH PRIOR AUTHORIZATION CRITERIA REVISED 6/1/05 Posted: 6/6/05 THERAPEUTIC PREFERRED NON-PREFERRED PA DRUG CLASS AGENTS AGENTS CRITERIA ACE INHIBITORS ACE INHIBITORS Four of the preferred agents must be tried for at least 30 days each ACEON (perindopril) ACCUPRIL (quinapril) before a non-preferred agent will be authorized unless one of the exceptions on the PA form is present. Implement 1/3/05 ALTACE (ramipril) CAPOTEN (captopril) benazepril fosinopril captopril LOTENSIN (benazepril) enalapril MONOPRIL (fosinopril) lisinopril PRINIVIL (lisinopril) MAVIK (trandolapril) quinapril moexepril UNIVASC (moexepril) VASOTEC (enalapril) ZESTRIL (lisinopril) ACE INHIBITOR/DIURETIC COMBINATIONS benazepril/HCTZ ACCURETIC (quinapril/HCTZ) captopril/HCTZ CAPOZIDE (captopril/HCTZ) enalapril/HCTZ LOTENSIN HCT (benazepril/HCTZ) lisinopril/HCTZ MONOPRIL HCT (fosinopril/HCTZ) UNIRETIC (moexepril/HCTZ) PRINZIDE (lisinopril/HCTZ) quinapril/HCTZ VASERETIC (enalapril/HCTZ) ZESTORETIC (lisinopril/HCTZ) ACE INHIBITOR/CALCIUM LOTREL (benazepril/amlodipine) LEXXEL (enalapril/felodipine) Each of the preferred agents must be tried for at least two weeks CHANNEL BLOCKER TARKA (trandolapril/verapamil) each before a non-preferred agent in that group will be authorized COMBINATIONS unless one of the exceptions on the PA form is present. Effective 7/1/05 ALZHEIMER’S AGENTS CHOLINESTERASE INHIBITORS Patients starting therapy in this class must show a documented ARICEPT (donepezil) COGNEX (tacrine) allergy to the preferred agents before a non-preferred agent will be authorized. Implement 10/1/04 EXELON (rivastigmine) REMINYL (galantamine) NMDA RECEPTOR ANTAGONIST NAMENDA (memantine) Unless otherwise specified, the listing of a particular brand or generic name includes all dosage forms of that drug.
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • G Protein-Coupled Receptors
    Alexander, S. P. H., Christopoulos, A., Davenport, A. P., Kelly, E., Marrion, N. V., Peters, J. A., Faccenda, E., Harding, S. D., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A. (2017). THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: G protein-coupled receptors. British Journal of Pharmacology, 174, S17-S129. https://doi.org/10.1111/bph.13878 Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1111/bph.13878 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Wiley at https://doi.org/10.1111/bph.13878 . Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2017/18: G protein-coupled receptors. British Journal of Pharmacology (2017) 174, S17–S129 THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: G protein-coupled receptors Stephen PH Alexander1, Arthur Christopoulos2, Anthony P Davenport3, Eamonn Kelly4, Neil V Marrion4, John A Peters5, Elena Faccenda6, Simon D Harding6,AdamJPawson6, Joanna L Sharman6, Christopher Southan6, Jamie A Davies6 and CGTP Collaborators 1 School of Life Sciences,
    [Show full text]
  • 2 12/ 35 74Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 22 March 2012 (22.03.2012) 2 12/ 35 74 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/16 (2006.01) A61K 9/51 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 9/14 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP201 1/065959 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 14 September 201 1 (14.09.201 1) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (25) Filing Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (26) Publication Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/382,653 14 September 2010 (14.09.2010) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, NANOLOGICA AB [SE/SE]; P.O Box 8182, S-104 20 ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Stockholm (SE).
    [Show full text]
  • WO 2014/151206 Al 25 September 2014 (25.09.2014) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/151206 Al 25 September 2014 (25.09.2014) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C07K 7/08 (2006.01) A61P 1/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 38/10 (2006.01) A61P 29/00 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, PCT/US20 14/025207 MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (22) International Filing Date: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 13 March 2014 (13.03.2014) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (25) Filing Language: English ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/790,266 15 March 2013 (15.03.2013) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/826,749 23 May 2013 (23.05.2013) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant: SYNERGY PHARMACEUTICALS INC.
    [Show full text]
  • Dr. James Murrough NCT03043560 Document Date: 6/12/2019
    Protocol EZOR61-01 Confidential SPONSOR: JAMES W. MURROUGH, MD INSTITUTION: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI (ISMMS) Clinical Trial Protocol DEVELOPING NEURONAL KCNQ CHANNEL MODULATORS FOR MOOD DISORDERS Protocol Number: EZOR61-01 Version #: 2.4 Version Date: 6/12/2019 Investigational Product: Ezogabine (Potiga, GlaxoSmithKline) IND Number: Exempt Development Phase: Phase IIa Sponsor: James W. Murrough, MD, PhD Assistant Professor of Psychiatry and Neuroscience Icahn School of Medicine at Mount Sinai 1 Gustave L. Levy Place, Box 1230 New York, New York 10029 Telephone: 212-585-4640 Funding Organization: National Institutes of Health (NIH)/ National Institute of Mental Health (NIMH) Principal Investigator: James W. Murrough, MD Assistant Professor of Psychiatry and Neuroscience Icahn School of Medicine at Mount Sinai 1 Gustave L. Levy Place, Box 1230 New York, New York 10029 Telephone: 212-585-4640 Fax: 212-241-3354 E-mail: [email protected] Medical Monitor: Dan V. Iosifescu, M.D., M.Sc. Associate Professor of Psychiatry NYU School of Medicine New York, NY 10016 Phone 646-754-5156 Fax 212-263-7460 [email protected] Coordinating Center: Icahn School of Medicine at Mount Sinai 1 Gustave L. Levy Place, Box 1230 New York, New York 10029 Participating site(s) Baylor College of Medicine Mood & Anxiety Disorders Program, Psychiatry PI: Sanjay Mathew, MD Version #: 2.4 Version Date: 6/12/2019 Page 1 of 66 Protocol EZOR61-01 Confidential Approval: PI or Sponsor Signature (Name and Title) Date This confidential information about an investigational product is provided for the exclusive use of investigators of this product and is subject to recall at any time.
    [Show full text]
  • Neurotensin Is a Proinflammatory Neuropeptide in Colonic Inflammation
    Neurotensin is a proinflammatory neuropeptide in colonic inflammation Ignazio Castagliuolo, … , Robert E. Carraway, Charalabos Pothoulakis J Clin Invest. 1999;103(6):843-849. https://doi.org/10.1172/JCI4217. Article The neuropeptide neurotensin mediates several intestinal functions, including chloride secretion, motility, and cellular growth. However, whether this peptide participates in intestinal inflammation is not known. Toxin A, an enterotoxin from Clostridium difficile, mediates pseudomembranous colitis in humans. In animal models, toxin A causes an acute inflammatory response characterized by activation of sensory neurons and intestinal nerves and immune cells of the lamina propria. Here we show that neurotensin and its receptor are elevated in the rat colonic mucosa following toxin A administration. Pretreatment of rats with the neurotensin receptor antagonist SR-48,692 inhibits toxin A–induced changes in colonic secretion, mucosal permeability, and histologic damage. Exposure of colonic explants to toxin A or neurotensin causes mast cell degranulation, which is inhibited by SR-48,692. Because substance P was previously shown to mediate mast cell activation, we examined whether substance P is involved in neurotensin-induced mast cell degranulation. Our results show that neurotensin-induced mast cell degranulation in colonic explants is inhibited by the substance P (neurokinin-1) receptor antagonist CP-96,345, indicating that colonic mast activation in response to neurotensin involves release of substance P. We conclude that neurotensin plays a key role in the pathogenesis of C. difficile–induced colonic inflammation and mast cell activation. Find the latest version: https://jci.me/4217/pdf Neurotensin is a proinflammatory neuropeptide in colonic inflammation Ignazio Castagliuolo,1 Chi-Chung Wang,1 Leyla Valenick,1 Asiya Pasha,1 Sigfus Nikulasson,2 Robert E.
    [Show full text]