DOCSLIB.ORG

Noradrenergic Suppression of Persistent Firing in Hippocampal CA1 Pyramidal Cells Through Camp-PKA Pathway

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Noradrenergic Suppression of Persistent Firing in Hippocampal CA1 Pyramidal Cells Through Camp-PKA Pathway Research Article: New Research | Neuronal Excitability Noradrenergic suppression of persistent firing in hippocampal CA1 pyramidal cells through cAMP-PKA pathway https://doi.org/10.1523/ENEURO.0440-20.2020 Cite as: eNeuro 2021; 10.1523/ENEURO.0440-20.2020 Received: 12 October 2020 Revised: 3 December 2020 Accepted: 20 December 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.eneuro.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 Valero-Aracama et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Noradrenergic suppression of persistent firing in hippocampal CA1 2 pyramidal cells through cAMP-PKA pathway 3 4 Abbreviated Title: Noradrenaline suppress persistent firing 5 6 1Ɨ 2,3Ɨ 2 3 7 Maria Jesus Valero-Aracama , Antonio Reboreda , Alberto Arboit , Magdalena Sauvage , Motoharu 2,3 * 8 Yoshida 9 1 10 Faculty of Psychology, Mercator Research Group - Structure of Memory, Ruhr-University Bochum, 11 44780 Bochum, Germany 12 Current affiliation: Institute for physiology and pathophysiology, University of Erlangen, Germany 13 2 14 German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany 15 3 16 Leibniz Institute for Neurobiology (LIN) 39118 Magdeburg, Germany 17 Ɨ Equal contributions ∗ 18 To whom correspondence should be addressed 19 20 Author contributions: 21 MY, AR, MJ and MS designed research; MJ, AR and AA performed research and analyzed data; 22 MJ, AR and MY wrote the paper. 23 24 Correspondence should be addressed to: 25 Dr Motoharu Yoshida 26 German Center for Neurodegenerative Diseases (DZNE) Magdeburg 27 Leipziger Str. 44 / Haus 64, 39120, Magdeburg, Germany 28 E-mail: [email protected] 29 30 Number of figures: 5 31 Number of tables: 2 32 Number of Multimedia: 0 33 Number of words for Abstract: 164 34 Number of words for Significance Statement: 35 Number of words for Introduction: 418 36 Number of words for Discussion: 1740 37 38 Acknowledgments: We thank Dr. Menno Witter for kindly sharing experimental procedures with us. 39 Conflict of Interest: Authors report no conflict of interest 40 Funding sources: This work was supported by the Mercator Stiftung and the German Research 41 Foundation (DFG) project YO177/4-1 and YO177/7-1. 42 1 43 Abstract 44 Persistent firing is believed to be a cellular correlate of working memory. While the effects of 45 noradrenaline (NA) on working memory have widely been described, its effect on the cellular 46 mechanisms of persistent firing remains largely unknown. Using in vitro intracellular recordings, we 47 demonstrate that persistent firing is supported by individual neurons in hippocampal CA1 pyramidal 48 cells through cholinergic receptor activation, but is dramatically attenuated by NA. In contrast to the 49 classical theory that recurrent synaptic excitation supports persistent firing, suppression of persistent 50 firing by NA was independent of synaptic transmission, indicating that the mechanism is intrinsic to 51 individual cells. In agreement with detrimental effects of cyclic adenosine monophosphate (cAMP) on 52 working memory, we demonstrate that the suppressive effect of NA was through cAMP-PKA pathway. 53 In addition, activation of β1 and/or β3 adrenergic receptors, which increases cAMP levels, 54 suppressed persistent firing. These results are in line with working memory decline observed during 55 high levels of NA and cAMP, which are implicated in high stress, aging and schizophrenia. 56 2 57 Significance Statement 58 While cholinergic modulation supports working memory, high concentrations of noradrenaline (NA), 59 which occurs under high stress for example, are detrimental for working memory. However, cellular 60 and molecular mechanisms underlying such working memory deficit remain largely unclear. In this 61 paper, we studied the effect of these two neuromodulators on persistent firing, the cellular correlate 62 of working memory. We demonstrate that a cholinergic receptor activation supports, while a 63 noradrenergic activation strongly inhibits persistent firing due to the PKA activation through specific 64 NA receptor types which upregulate cAMP. These data are in line with working memory deficits in 65 aging and schizophrenia in which cAMP levels are altered, and indicate potential intrinsic cellular 66 mechanism of working memory impairment. 67 68 Introduction 69 Persistent firing is a cellular response characterized by repetitive spiking that outlasts triggering 70 stimulus, and is believed to be a neural base of working memory (Goldman-Rakic, 1995; Major & 71 Tank, 2004). Persistent firing observed in humans and animals in vivo during working memory tasks 72 correlate with the task performance (Bukalo et al., 2004; Colombo & Gross, 1994; Funahashi, Bruce, 73 & Goldman-Rakic, 1989; Hampson & Deadwyler, 2003; Kamiński et al., 2017). In contrast to the 74 classical hypothesis that persistent firing is supported by recurrent excitatory synaptic connections, 75 recent studies have shown that persistent firing can also be supported in individual cells (Egorov, 76 Hamam, Fransén, Hasselmo, & Alonso, 2002; Jochems & Yoshida, 2013; Knauer, Jochems, Valero- 77 Aracama, & Yoshida, 2013). These studies in general used cholinergic receptor activations to induce 78 persistent firing, which is in agreement with the supportive role of acetylcholine on working memory 79 (Reboreda et al., 2018). However, roles of other neuromodulators such as the noradrenaline (NA) on 80 this type of persistent firing largely remain to be studied. 81 While cholinergic modulation generally supports working memory (Kaneko & Thompson, 82 1997; Weiss et al., 2000), NA could be detrimental for working memory (Arnsten, 2009; Roozendaal 83 & McGaugh, 2011). High levels of NA are usually present during states of stress (Bremner, Krystal, 84 Southwick, & Charney, 1996), which are known to impair working memory (Arnsten, Wang, & 85 Paspalas, 2012; Diamond, Ingersoll, Fleshner, & Rose, 1996; Qin, Hermans, van Marle, Luo, & 86 Fernández, 2009; Schoofs, Preuß, & Wolf, 2008). At the receptor subtype levels, β1 and α2 87 adrenoreceptors, which are positively and negatively coupled to cAMP signaling, impair and facilitate 88 working memory, respectively (Arnsten & Li, 2005; Jäkälä et al., 1999; Li, Mao, Wang, & Mei, 1999; 3 89 Ma, Qi, Peng, & Li, 2003; Ramos et al., 2005). In addition, elevated and decreased cAMP levels impair 90 and enhance, respectively, working memory performance (Arnsten, Mathew, Ubriani, Taylor, & Li, 91 1999; Runyan, Moore, & Dash, 2005; Taylor, Birnbaum, Ubriani, & Arnsten, 1999; M. Wang et al., 92 2007). Moreover, upregulated cAMP levels are associated with working memory impairment in aging 93 and schizophrenia (Barch & Ceaser, n.d.; Millar, 2005; M. Wang et al., 2011). Raising cAMP levels 94 would increase PKA activation that also is negatively correlated to working memory performance 95 (Kobori, Moore, & Dash, 2015), together supporting the importance of NA and cAMP-PKA in working 96 memory. 97 At the cellular level, a supportive role of NA on persistent firing through a reduction of cAMP 98 levels has been observed in the prefrontal cortex (PFC, Zizhen Zhang, Cordeiro Matos, Jego, 99 Adamantidis, & Séguéla, 2013). In addition, elevated cAMP levels caused a suppression of the 100 calcium-activated nonspecific cation (CAN) current and persistent firing in the PFC and hippocampus 101 (El-Hassar, Hagenston, D’Angelo, & Yeckel, 2011; Sidiropoulou et al., 2009; Zizhen Zhang et al., 2013). 102 However, it remains unclear whether NA has a supportive or detrimental effect on persistent firing in 103 the hippocampus. 104 We therefore tested the effects of cholinergic and noradrenergic receptor activation in both 105 induction and modulation of persistent firing in individual hippocampal CA1 pyramidal cells in mice. 106 We find that a noradrenergic stimulation strongly inhibits persistent firing while a cholinergic 107 activation supports it. In addition, the noradrenergic suppression of persistent firing is independent 108 of ionotropic synaptic transmission, but is through the cAMP-PKA pathway. We further demonstrate 109 specific NA receptor subtypes involved in this suppression. These observations indicate that high NA 110 and cAMP conditions, which often suppress working memory through PKA activation, also suppress 111 cellular mechanisms for persistent firing in the hippocampus. 112 113 Methods 114 115 All the experimental designs were approved by the local ethic committee (Der Tierschutzbeauftragte, 116 Ruhr-Universität Bochum, and Deutsches Zentrum für Neurodegenerative Erkrankungen) and carried 117 out in accordance with the European Communities Council Directive of September 22nd, 2010 118 (2010/63/EU). 119 120 Slice preparation 121 Acute hippocampal slices were obtained from adult (2 - 4 month) C57BL6 female mice (Charles 122 River). Animals were deeply anesthetized (intraperitoneal injection of 120 mg/Kg of ketamine and 16 123 mg/Kg of xylazin) and intracardiac perfusion with ice-cold modified artificial cerebrospinal fluid 4 124 (mACSF) was conducted
Load more

Recommended publications
  • Cell Line Descriptions Geneblazer® M1-NFAT
    Version No.: GeneBLAzer ® Validation Packet Page 1 of 5 01Sep08 Optimization of the GeneBLazer ® M1-NFAT-bla Jurkat Cell Line GeneBLAzer ® M1 NFAT-bla Jurkat Cells Catalog Numbers – K1710 Cell Line Descriptions GeneBLAzer ® M1-NFAT-bla Jurkat cells contain the human Acetylcholine (muscarinic) subtype 1 receptor (M1), (Accession # NM_000738 ) stably integrated into the CellSensor ® NFAT-bla Jurkat cell line. CellSensor ® NFAT-bla Jurkat cells (Cat. no. K1671) contain a beta-lactamase (bla ) reporter gene under control of the Nuclear Factor of Activated T-cells (NFAT) response element. M1-NFAT-bla Jurkat cells are functionally validated for Z’-factor and EC 50 concentrations of carbachol (Figure 1). In addition, GeneBLAzer ® M1-NFAT-bla CHO-K1 cells have been tested for assay performance under variable conditions. Target Description Muscarinic acetylcholine receptors are members of the G protein-coupled receptor (GPCR) superfamily. Muscarinic receptors are widely distributed and mediate the actions of acetylcholine in both the CNS and peripheral tissues. Five muscarinic receptor subtypes have been identified and are referred to as M 1-M5 (1-5). The five genes that encode the muscarinic receptors all belong to the rhodopsin-line family (Family A) and share strong sequence homology but have unique regions located at the amino terminus (extracellular) and in the third intracellular loop. The M 1, M3, and M 5 receptor subtypes couple through the G q/11 class of G-proteins and activate the phopholipase C pathway. Activation of this pathway in turn leads to increases in free intracellular calcium levels as inositol triphosphate mediates release of calcium from the endoplasmic reticulum.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2006/0110449 A1 Lorber Et Al
    US 200601 10449A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0110449 A1 LOrber et al. (43) Pub. Date: May 25, 2006 (54) PHARMACEUTICAL COMPOSITION Publication Classification (76) Inventors: Richard R. Lorber, Scotch Plains, NJ (US); Heribert W. Staudinger, Union, (51) Int. Cl. NJ (US); Robert E. Ward, Summit, NJ A6II 3/473 (2006.01) (US) A6II 3L/24 (2006.01) Correspondence Address: A6IR 9/20 (2006.01) SCHERING-PLOUGH CORPORATION (52) U.S. Cl. ........................... 424/464; 514/290: 514/540 PATENT DEPARTMENT (K-6-1, 1990) 2000 GALLOPNG HILL ROAD KENILWORTH, NJ 07033-0530 (US) (57) ABSTRACT (21) Appl. No.: 11/257,348 (22) Filed: Oct. 24, 2005 The present invention relates to formulations useful for Related U.S. Application Data treating respiratory disorders associated with the production of mucus glycoprotein, skin disorders, and allergic conjunc (60) Provisional application No. 60/622,507, filed on Oct. tivitis while substantially reducing adverse effects associ 27, 2004. Provisional application No. 60/621,783, ated with the administration of non-selective anti-cholin filed on Oct. 25, 2004. ergic agents and methods of use thereof. US 2006/01 10449 A1 May 25, 2006 PHARMACEUTICAL COMPOSITION example, Weinstein and Weinstein (U.S. Pat. No. 6,086,914) describe methods of treating allergic rhinitis using an anti CROSS REFERENCE TO RELATED cholinergic agent with a limited capacity to pass across lipid APPLICATION membranes, such as the blood-brain barrier, in combination with an antihistamine that is limited in both sedating and 0001. This application claims benefit of priority to U.S.
    [Show full text]
  • In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs As Inverse H1 Receptor Agonists
    0022-3565/07/3221-172–179$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 322, No. 1 Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics 118869/3215703 JPET 322:172–179, 2007 Printed in U.S.A. In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs as Inverse H1 Receptor Agonists R. A. Bakker,1 M. W. Nicholas,2 T. T. Smith, E. S. Burstein, U. Hacksell, H. Timmerman, R. Leurs, M. R. Brann, and D. M. Weiner Department of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.A.B., H.T., R.L.); ACADIA Pharmaceuticals Inc., San Diego, California (R.A.B., M.W.N., T.T.S., E.S.B., U.H., M.R.B., D.M.W.); and Departments of Pharmacology (M.R.B.), Neurosciences (D.M.W.), and Psychiatry (D.M.W.), University of California, San Diego, California Received January 2, 2007; accepted March 30, 2007 Downloaded from ABSTRACT The human histamine H1 receptor (H1R) is a prototypical G on this screen, we have reported on the identification of 8R- protein-coupled receptor and an important, well characterized lisuride as a potent stereospecific partial H1R agonist (Mol target for the development of antagonists to treat allergic con- Pharmacol 65:538–549, 2004). In contrast, herein we report on jpet.aspetjournals.org ditions. Many neuropsychiatric drugs are also known to po- a large number of varied clinical and chemical classes of drugs tently antagonize this receptor, underlying aspects of their side that are active in the central nervous system that display potent effect profiles.
    [Show full text]
  • TE INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub
    US 20200187851A1TE INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No .: US 2020/0187851 A1 Offenbacher et al. (43 ) Pub . Date : Jun . 18 , 2020 ( 54 ) PERIODONTAL DISEASE STRATIFICATION (52 ) U.S. CI. AND USES THEREOF CPC A61B 5/4552 (2013.01 ) ; G16H 20/10 ( 71) Applicant: The University of North Carolina at ( 2018.01) ; A61B 5/7275 ( 2013.01) ; A61B Chapel Hill , Chapel Hill , NC (US ) 5/7264 ( 2013.01 ) ( 72 ) Inventors: Steven Offenbacher, Chapel Hill , NC (US ) ; Thiago Morelli , Durham , NC ( 57 ) ABSTRACT (US ) ; Kevin Lee Moss, Graham , NC ( US ) ; James Douglas Beck , Chapel Described herein are methods of classifying periodontal Hill , NC (US ) patients and individual teeth . For example , disclosed is a method of diagnosing periodontal disease and / or risk of ( 21) Appl. No .: 16 /713,874 tooth loss in a subject that involves classifying teeth into one of 7 classes of periodontal disease. The method can include ( 22 ) Filed : Dec. 13 , 2019 the step of performing a dental examination on a patient and Related U.S. Application Data determining a periodontal profile class ( PPC ) . The method can further include the step of determining for each tooth a ( 60 ) Provisional application No.62 / 780,675 , filed on Dec. Tooth Profile Class ( TPC ) . The PPC and TPC can be used 17 , 2018 together to generate a composite risk score for an individual, which is referred to herein as the Index of Periodontal Risk Publication Classification ( IPR ) . In some embodiments , each stage of the disclosed (51 ) Int. Cl. PPC system is characterized by unique single nucleotide A61B 5/00 ( 2006.01 ) polymorphisms (SNPs ) associated with unique pathways , G16H 20/10 ( 2006.01 ) identifying unique druggable targets for each stage .
    [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]
  • (Ph OH N N Me O YO O YO
    US 20070265293A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0265293 A1 Boyd et al. (43) Pub. Date: Nov. 15, 2007 (54) (S)-N-METHYLNALTREXONE Publication Classification (76) Inventors: Thomas A. Boyd, Grandview, NY (51) Int. Cl. (US); Howard Wagoner, Warwick, NY A6II 3L/4355 (2006.01) (US); Suketu P. Sanghvi, Kendall Park, A6M II/00 (2006.01) NJ (US); Christopher Verbicky, A6M I5/08 (2006.01) Broadalbin, NY (US); Stephen 39t. 35O C Andruski, Clifton Park, NY (US) (2006.01) A6IP 3L/00 (2006.01) Correspondence Address: St. 4. CR WOLF GREENFIELD & SACKS, P.C. (2006.01) 6OO ATLANTIC AVENUE 3G (i. 308: BOSTON, MA 02210-2206 (US) A6IP 33/02 (2006.01) C07D 489/00 (2006.01) (21) Appl. No.: 11/441,452 (52) U.S. Cl. .............. 514/282; 128/200.23; 128/202.17; (22) Filed: May 25, 2006 546/45 Related U.S. Application Data (57) ABSTRACT This invention relates to S-MNTX, methods of producing (60) Provisional application No. 60/684,570, filed on May S-MNTX, pharmaceutical preparations comprising 25, 2005. S-MNTX and methods for their use. O G M Br Br e (pH OH N N Me O YO O YO OH OH R-MNTX S-MNTX Patent Application Publication Nov. 15, 2007 Sheet 1 of 6 US 2007/0265293 A1 Fig. 1 OH OH Me-N Me-N D / O O -----BBr, O O CHCI NMP, 3 AUTOCLAVE, 70'C OMe OH 1 2 Br OH As GE) G As 69 GOH Me-N ION Me-N -lass O SO EXCHANGE O SO OH OH 3 S-MNTX 1 - OXYCODONE 2 - OXYMORPHONE 3 - ODIDE SALT OF S-MNTX Fig.
    [Show full text]
  • In Gtopdb V.2021.2
    IUPHAR/BPS Guide to Pharmacology CITE https://doi.org/10.2218/gtopdb/F2/2021.2 Acetylcholine receptors (muscarinic) in GtoPdb v.2021.2 Nigel J. M. Birdsall1, Sophie Bradley2, David A. Brown3, Noel J. Buckley4, R.A. John Challiss2, Arthur Christopoulos5, Richard M. Eglen6, Frederick Ehlert7, Christian C. Felder8, Rudolf Hammer9, Heinz J. Kilbinger10, Günter Lambrecht11, Chris Langmead5, Fred Mitchelson12, Ernst Mutschler11, Neil M. Nathanson13, Roy D. Schwarz14, David Thal5, Andrew B. Tobin2, Celine Valant5 and Jurgen Wess15 1. Francis Crick Institute, UK 2. University of Leicester, UK 3. University College London, UK 4. King's College London, UK 5. Monash University, Australia 6. PerkinElmer, UK 7. University of California Irvine, USA 8. Lilly Research Laboratories, USA 9. Nippon Boehringer Ingleheim, Japan 10. University of Mainz, Germany 11. University of Frankfurt, Germany 12. University of Melbourne, Australia 13. University of Washington, USA 14. Pfizer, USA 15. National Institutes of Health, USA Abstract Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [50]) are activated by the endogenous agonist acetylcholine. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates. I Contents This is a citation summary for Acetylcholine receptors (muscarinic) in the Guide to Pharmacology database (GtoPdb).
    [Show full text]
  • United States Patent (10) Patent No.: US 8,003,794 B2 Boyd Et Al
    USO08003794B2 (12) United States Patent (10) Patent No.: US 8,003,794 B2 Boyd et al. (45) Date of Patent: Aug. 23, 2011 (54) (S)-N-METHYLNALTREXONE 4.385,078 A 5/1983 Onda et al. 4.427,676 A 1, 1984 White et al. (75) Inventors: Thomas A. Boyd, Grandview, NY (US); 4,430,327 A 2, 1984 Frederickson et al. 4,452,775 A 6, 1984 Kent Howard Wagoner, Warwick, NY (US); 4,457.907. A 7/1984 Porter et al. Suketu P. Sanghvi, Kendall Park, NJ 4.462,839 A 7/1984 McGinley et al. (US); Christopher Verbicky, 4,466,968 A 8, 1984 Bernstein Broadalbin, NY (US); Stephen t St. A s 3. Miley al. Andruski, Clifton Park, NY (US) 4,556,552- - - A 12/1985 Porter2 et al.a. 4,606,909 A 8/1986 Bechgaard et al. (73) Assignee: Progenics Pharmaceuticals, Inc., 4,615,885 A 10/1986 Nakagame et al. Tarrytown, NY (US) 4,670.287. A 6/1987 Tsuji et al. 4.675, 189 A 6, 1987 Kent et al. (*) Notice: Subject to any disclaimer, the term of this 4,689,332 A 8/1987 McLaughlin et al. patent is extended or adjusted under 35 2.7868 A SE Se U.S.C. 154(b) by 184 days. 4,765,978 A 8/1988 Abidi et al. 4,806,556 A 2/1989 Portoghese (21) Appl. No.: 12/460,507 4,824,853. A 4, 1989 Walls et al. 4,836,212 A 6, 1989 Schmitt et al. (22) Filed: Jul. 20, 2009 4,837.214 A 6, 1989 Tanaka et al.
    [Show full text]
  • Towards the Synthesis of Aromatic Analogues of Himbacine, Potential Muscarinic Ligands
    TOWARDS THE SYNTHESIS OF AROMATIC ANALOGUES OF HIMBACINE, POTENTIAL MUSCARINIC LIGANDS A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy by Xue Qin Shi (B.E., M.Sc.) Supervisor: Associate Professor Roger W. Read SCHOOL OF CHEMISTRY THE UNIVERSITY OF NEW SOUTH WALES MAY2000 CERTIFICATE OF ORIGNALITY I hereby declare thatthis submission is my own workand that, to the best of my knowledge and belief, it contains no material previously published or written by another person nor material which to a substantial extent has been accepted for the award of any other degree or diploma of a university or other institute of higher learning, except where due acknowledgementis made in thetext . CERTIFICATEOF ORIGINALITY I hereby declare that this submission is my own worlc and to the best of my knowledge it contains no materials previously published or written by another person, nor material which to a substantial extent bas been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. AJJ.y contnbution made to the research by others, with whom I have worlced at UNSW or elsewhere. is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged. 11 ACKNOLEDGEMENTS I am very grateful to my supervisor Associate Professor Roger W.
    [Show full text]
  • A Straightforward Route to Enantiopure Pyrrolizidines And
    Molecules 2001, 6, 142-193 molecules ISSN 1420-3049 http://www.mdpi.org Review Muscarinic Receptor Agonists and Antagonists Kenneth J. Broadley1 and David R. Kelly2,* 1Division of Pharmacology, Welsh School of Pharmacy and 2Department of Chemistry, Cardiff University, Cathays Park, Cardiff, CF10 3TB, UK *To whom correspondence should be addressed; e-mail: [email protected] Received: 2 August 2000; in revised form 16 January 2001 / Accepted: 16 January 2001 / Published: 28 February 2001 Abstract: A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes). Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted. Keywords: Alzheimer’s disease, nicotine, acetylcholine, arecoline, himbacine, tacrine, cyclostelletamines, intramolecular Diels-Alder reaction, indole alkaloids Contents 1 The Pharmacology of Muscarinic Receptors 1.1 Introduction 1.2 Muscarinic receptor subtypes Molecules 2001, 6 143 2 Pharmacological Effects of Agonists and Therapeutic Applications 2.1 Cardiovascular system 2.2 Gastointestinal tract 2.3 Other smooth muscle 2.4 Glandular secretions 2.5 The eye 2.6 Central nervous
    [Show full text]
  • V10a93-Yin Pgmkr
    Molecular Vision 2004; 10:787-93 <http://www.molvis.org/molvis/v10/a93> ©2004 Molecular Vision Received 22 December 2003 | Accepted 19 August 2004 | Published 13 October 2004 Muscarinic antagonist control of myopia: A molecular search for the M1 receptor in chick George C. Yin, Alex Gentle, Neville A. McBrien Department of Optometry and Vision Sciences, The University of Melbourne, Victoria, Australia Purpose: Pirenzepine, an M1 selective muscarinic antagonist, is effective in slowing the progression of myopia in both humans and experimental animals, including chick. As an M1 selective antagonist, pirenzepine is considered to mediate its effect through M1 receptors. However, there is currently no report of the M1 receptor in chicken. Therefore, if the mechanism of action of pirenzepine is similar across species, either the drug mediates its effect through a non-M1 mecha- nism, or M1 muscarinic receptors are present in chicken. The aim of the present study was to determine whether a genetic template for the M1 receptor was expressed, or even present, in chick. Methods: Polymerase Chain Reaction (PCR), and Southern and northern blotting analyses were used to search for M1 mRNA in chick ocular and brain tissues. PCR and Southern analyses were then used for searching the chick M1 gene and promoter. Appropriate rat positive controls were included throughout the study. Results: Direct mRNA detection by northern analysis showed no evidence of M1 mRNA expression in the chick ocular and brain tissues studied. Identical results were obtained from PCR amplification and were further confirmed by Southern analysis. Similarly, no M1 gene or promoter sequences were detected by PCR or Southern analyses.
    [Show full text]
  • Muscarinic Receptor Functioning and Distribution in The
    Muscarinic receptor GREGOR W. NIETGEN, JOERG SCHMIDT, LUTZ HESSE, CHRISTIAN W. HONEMANN, functioning and MARCEL E. DURIEUX distribution in the eye: molecular basis and implications for clinical diagnosis and therapy The role of neurotransmitters has generated number of receptors (cholinergic, adrenergic considerable interest over the last decade. and others) have been found in all types of Dale's first description in 1914 of the muscarinic ocular tissue: the functional consequence of and nicotinic components of the cholinergic their activation remains elusive but is currently systeml provided an explanation for the effects being investigated with great zeal. Glaucoma of various cholinergic active drugs on the eye. patients are still being treated with pilocarpine G.w. Nietgen J. Schmidt Parasympathetic cholinergic input to the human almost 40 years5 after its introduction to western L. Hesse iris sphincter muscle comes from neurons medicine in 1875.6 The development of specific Zentrum fOr whose axons make up the ciliary nerve, a muscarinic agonists (acetyl-j3-methylcholine) Augenheilkunde branch of the third cranial nerve. Acetylcholine and antagonists (scopolamine) followed. Philipps-Universitat Marburg is released by these neurons onto their target Cholinesterase was discovered in 19267 and Marburg, Germany 8 cells, the smooth muscle surrounding the pupil. named in 1932. At the same time carbachol was C.W. Honemann Muscarinic acetylcholine receptors on the synthesised,9 a drug resistant to cholinesterases M.E. Durieux surface of the muscle cells transduce the with a suitable specificity for glaucoma Departments of chemical signal into a muscle contraction which treatment.IO,ll Over the years various Pharmacology, Anaesthesiology and constricts the pupil.
    [Show full text]