DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 8,058,243 B2 Tyers Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent No.: US 8,058,243 B2 Tyers Et Al USOO8058243B2 (12) United States Patent (10) Patent No.: US 8,058,243 B2 Tyers et al. (45) Date of Patent: Nov. 15, 2011 (54) METHOD FORTREATING A BRAIN CANCER Corcoran et al., “A mouse model for medulloblastoma and basal cell WITH IFENPRODIL nevus syndrome” J. Neuro-oncol., 53(3):307-318 (Jul. 2001). Dalton et al., “Depression and cancer risk: a register-based study of patients hospitalized with affective disorders, Denmark, 1969-1993.” (75) Inventors: Mike Tyers, Toronto (CA); Phedias Am. J. Epidemiol. 155(12): 1088-1095 (Jun. 15, 2002). Diamandis, Toronto (CA); Peter B. Dalton et al., “Risk for cancer in a cohort of patients hospitalized for Dirks, Toronto (CA) schizophrenia in Denmark, 1969-1993.” Schizophr. Res., 75(2- 3):315-324 (Jun. 15, 2005; e-pub: Dec. 13, 2004). (73) Assignees: HSC Research and Development Ding et al., “A role for chemistry in stem cell biology” Nat. Limited Partnership (CA); Mount Biotechnol. 22(7):833-840 (Jul 2004; e-pub: Jun. 30, 2004). Sinai Hospital (CA) Diamandis et al., "Chemical genetics reveals a complex functional ground state of neural stem cells' Nat. Chem. Biol. 3(5):268-273 (*) Notice: Subject to any disclaimer, the term of this (May 2007; e-pub: Apr. 8, 2007). patent is extended or adjusted under 35 Encinas et al., “Fluoxetine targets early progenitor cells in the adult brain” Proc. Natl. Acad. Sci. USA, 103(21):8233-8238 (May 23, U.S.C. 154(b) by 604 days. 2006; e-pub: May 15, 2006). Enver et al., “Loops, lineage, and leukemia' Cell, 94(1):9-12 (Jul. 10, (21) Appl. No.: 11/871,562 1998). Galanis et al., "Chemotherapy for high-grade gliomas' Br. J. Cancer, (22) Filed: Oct. 12, 2007 82(8): 1371-1380 (Apr. 2000). Galli et al., “Isolation and characterization of tumorigenic, stem-like (65) Prior Publication Data neural precursors from human glioblastoma Cancer Res., 64(19):701 1-7021 (Oct. 1, 2004). US 2009/0076O19 A1 Mar. 19, 2009 Ge et al., “GABA sets the tempo for activity-dependent adult neurogenesis' Trends Neurosci., 30(1): 1-8 (Jan. 2007; e-pub: Nov. Related U.S. Application Data 20, 2006). Goldacre et al., “Schizophrenia and cancer: an epidemiological (60) Provisional application No. 60/851,615, filed on Oct. study”. Br. J. Psychiatry, 187:334-338 (Oct. 2005). 13, 2006. Gritti et al., “Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like popula tion from the subventricular region of the adult mouse forebrain' J. (51) Int. Cl. Neurosci., 19(9):3287-3297 (May 1, 1999). A6IP35/00 (2006.01) Groszer et al., “PTEN negatively regulates neural stem cell self CI2N5/095 (2010.01) renewal by modulating Go-Gi cell cycle entry” Proc. Natl. Acad. Sci. (52) U.S. Cl. ....... 514/19.3; 435/377: 514/18.1; 558/483 USA, 103(1):111-116 (Jan. 3, 2006; e-pub: Dec. 22, 2005). (58) Field of Classification Search ........................ None Hagell et al., “Apomorphine in the treatment of Parkinson's disease” J. Neurosci. Nurs. 33(1): 21-34, 37-38 (Feb. 2001). See application file for complete search history. Hagg T., “Molecular regulation of adult CNS neurogenesis: an inte grated view” Trends Neurosci., 28(11): 589-95 (Nov. 2005; e-pub: (56) References Cited Sep. 8, 2005). Harrist et al., “Alteration of hippocampal cell proliferation in mice U.S. PATENT DOCUMENTS lacking the f2 subunit of the neuronal nicotinic acetylcholine recep 2005/0054650 A1 3f2005 Ikonomidou ................. 514,249 tor” Synapse, 54(4):200-206 (Dec. 15, 2004). Hemmati et al., “Cancerous stem cells can arise from pediatric brain OTHER PUBLICATIONS tumors” Proc. Natl. Acad. Sci. USA, 100(25): 15178-15183 (Dec. 9, 2003; e-pub: Nov. 26, 2003). Ohgaki et al., Cancer Science, 100(12): 2235-2241, Dec. 2009.* Hertz et al., “Receptor expression in primary cultures of neurons or Ahn et al., “In vivo analysis of quiescent adult neural stem cells astrocytes' Prog. Neuropsychopharmacol. Biol. Psychiatry, 8(4- responding to Sonic hedgehog' Nature, 437(3994):894-897 (Oct. 6):521-527 (1984). 2005). Hitoshi et al., “Notch pathway molecules are essential for the main Baker et al., “Dopaminergic nigrostriatal projections regulate neural tenance, but not the generation, of mammalian neural stem cells' precursor proliferation in the adult mouse subventricular Zone” Eur J Genes Dev., 16(7):846-58 (Apr. 1, 2002). Neurosci., 2002):575-579 (Jul 2004). Bao et al., "Glioma stem cells promote radioresistance by preferen (Continued) tial activation of the DNA damage response” Nature,444(7120):756 760 (Dec. 7, 2006; e-pub: Oct. 18, 2006). Primary Examiner — Lorraine Spector Barak et al., “Reduced cancer incidence among patients with Schizo Assistant Examiner — Stacey MacFarlane phrenia Cancer, 104(12):2817-2821 (Dec. 15, 2005). Burger et al., “Glioblastoma multiforme and anaplastic astrocytoma. (74) Attorney, Agent, or Firm — Howson & Howson LLP Pathologic criteria and prognostic implications' Cancer, 56(5): 1106 (57) ABSTRACT 1111 (Sep. 1, 1985). Berman et al., “Medulloblastoma growth inhibition by hedgehog A clonogenic neurosphere assay is described that carries out pathway blockade” Science, 297(5586): 1559-1561 (Aug. 30, 2002). high throughput screens (HTS) to identify potent and/or Carney et al., “Occurrence of cancer among people with mental selective modulators of proliferation, differentiation and/or health claims in an insured population” Psychosom Med., 66(5):735 743 (Sep.-Oct. 2004). renewal of neural precursor cells, neural progenitor cells and/ Chen et al., “Self-renewal of embryonic stem cells by a small mol or self-renewing and multipotent neural stem cells (NSCs). ecule” Proc. Natl. Acad. Sci. USA., 103(46): 17266-17271 (Nov. 14, Compositions comprising the identified modulators and 2006; e-pub Nov. 6, 2006). methods of using the modulators and compositions, in par Cohen et al., “Food and Drug Administration Drug approval Sum ticular to treat neurological disorders (e.g. brain or CNS can mary: temozolomide plus radiation therapy for the treatment of cer) or damage are also disclosed. newly diagnosed glioblastoma multiforme” Clin. Cancer Res., 11(19 pt 1):6767-6771 (Oct. 1, 2005). 4 Claims, 26 Drawing Sheets US 8,058,243 B2 Page 2 OTHER PUBLICATIONS Reynolds et al., “Clonal and population analyses demonstrate that an Höglinger et al., “Dopamine depletion impairs precursor cell prolif EGF-responsive mammalian embryonic CNS precursor is a stem eration in Parkinson disease” Nat. Neurosci., 7(7):726-735 (Jul. cell” Dev. Biol., 175(90): 1-13 (Apr. 10, 1996). 2004; e-pub Jun. 13, 2004). Reynolds et al., “Neural stem cells and neurospheres—re-evaluating Iacovelli et al., “Pharmacological activation of mGlu4 metabotropic the relationship'Nat. Methods, 2(5):333-336 (May 2005; e-pub: Apr. glutamate receptors inhibits the growth of medulloblastomas' J. 21, 2005). Neurosci., 26(32): 8388-8397 (Aug. 9, 2006). Santos et al., “Stemness:Transcriptional profiling of embryonic and Kevorkov et al., “Statistical analysis of systematic errors in high throughput screening” J. Biomol. Screen., 10(6):557-567 (Sep. 2005; adult stem cells' Science, 298(5593):597-600 (Oct. 18, 2002; e-pub: e-pub Aug. 15, 2005). Sep. 12, 2002). Kippin et al., “Dopamine specifically inhibits forebrain neural stem Santarelli et al., “Requirement of hippocampal neurogenesis for the cell proliferation, Suggesting a novel effect of antipsychotic drugs' J. behavioral effects of antidepressants' Science, 301(5634):805-809 Neurosci., 25(24):5815-5823 (Jun. 15, 2005). (Aug. 8, 2003). Lalonde et al., “Are dopamine antagonists a risk factor for breast Seifert et al., “Astrocyte dysfunction in neurological disorders: a cancer? An answer from Parkinson's disease' Breast, 12(4):280-282 molecular perspective” Nat. Rev. Neurosci., 7(3): 194-206 (Mar. (Aug. 2003). 2006). Lee et al., “Tumor stem cells derived from glioblastomas cultured in Sharomet al., “From large networks to small molecules' Curr. Opin. bFGF and EGF more closely mirror the phenotype and genotype of Chem. Biol. 8(1): 81-90 (Feb. 2004). primary tumors than do serum-cultured cell lines' Cancer Cell, Singh et al., “Identification of human brain tumour initiating cells' 9(5):391-403 (May 2006). Nature, 432: 396–401 (Nov. 18, 2004). Lie et al., “Wnt signalling regulates adult hippocampal Singh et al., “Identification of a cancer stem cell in human brain neurogenesis” Nature, 437:1370-1375 (Oct. 27, 2005). tumors' Cancer Res., 63(18):5821-5828 (Sep. 15, 2003). Lledo et al., “Adult neurogenesis and functional plasticity in neuronal circuits' Nat. Rev. Neurosci., 7(3): 179-193 (Mar. 2006). Taylor et al., “Radial glia cells are candidate stem cells of MacDonald et al., “Identifying off-target effects and hidden pheno ependymoma Cancer Cell, 8:323-335 (Oct. 17, 2005). types of drugs in human cells' Nat. Chem. Biol. 2(6):329-337 (Jun. Tropepe et al., “Distinct neural stem cells proliferate in response to 2006; e-pub: May 7, 2006). EGF and FGF in the developing mouse telencephalon” Dev. Biol. Molofsky et al., “Bmi-1 dependence distinguishes neural stem cell 208(1):166-188 (Apr. 1, 1999). self-renewal from progenitor proliferation” Nature, 425(6961): 962 Uchida et al., “Direct isolation of human central nervous system stem 967 (Oct. 30, 2003; e-pub: Oct. 22, 2003). cells' Proc. Natl. Acad. Sci. USA, 97(26): 14720-14725 (Dec. 19, Nacher et al., “NMDA receptor antagonist treatment increases the 2000). production of new neurons in the aged rathippocampus' Neurobiol. Vescoviet al., “Brain tumour stem cells' Nat. Rev. Cancer, 6(6);425 Aging, 24(2):273-284 (Mar.-Apr. 2003). 436 (Jun. 2006). Newlands et al., "Temozolomide: a review of its discovery, chemical Wishart et al., “DrugBank: a comprehensive resource for in silico properties, pre-clinical development and clinical trials' Cancer Treat drug discovery and exploration” Nucleic Acids Res., 34(Database Rev.
Load more

Recommended publications
  • (12) Patent Application Publication (10) Pub. No.: US 2004/0224020 A1 Schoenhard (43) Pub
    US 2004O224020A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0224020 A1 Schoenhard (43) Pub. Date: Nov. 11, 2004 (54) ORAL DOSAGE FORMS WITH (22) Filed: Dec. 18, 2003 THERAPEUTICALLY ACTIVE AGENTS IN CONTROLLED RELEASE CORES AND Related U.S. Application Data IMMEDIATE RELEASE GELATIN CAPSULE COATS (60) Provisional application No. 60/434,839, filed on Dec. 18, 2002. (76) Inventor: Grant L. Schoenhard, San Carlos, CA (US) Publication Classification Correspondence Address: (51) Int. Cl. ................................................... A61K 9/24 Janet M. McNicholas (52) U.S. Cl. .............................................................. 424/471 McAndrews, Held & Malloy, Ltd. 34th Floor (57) ABSTRACT 500 W. Madison Street Chicago, IL 60661 (US) The present invention relates to oral dosage form with active agents in controlled release cores and in immediate release (21) Appl. No.: 10/742,672 gelatin capsule coats. Patent Application Publication Nov. 11, 2004 Sheet 1 of 3 US 2004/0224020 A1 r N 2.S Hr s Patent Application Publication Nov. 11, 2004 Sheet 2 of 3 US 2004/0224020 A1 r CN -8 e N va N . t Cd NOLLYRILNONOO Patent Application Publication Nov. 11, 2004 Sheet 3 of 3 US 2004/0224020 A1 US 2004/0224020 A1 Nov. 11, 2004 ORAL DOSAGE FORMS WITH released formulations, a long t is particularly disadvan THERAPEUTICALLY ACTIVE AGENTS IN tageous to patients Seeking urgent treatment and to maintain CONTROLLED RELEASE CORES AND MEC levels. A second difference in the pharmacokinetic IMMEDIATE RELEASE GELATIN CAPSULE profiles of controlled release in comparison to immediate COATS release drug formulations is that the duration of Sustained plasma levels is longer in the controlled release formula CROSS REFERENCED APPLICATIONS tions.
    [Show full text]
  • INVESTIGATION of NATURAL PRODUCT SCAFFOLDS for the DEVELOPMENT of OPIOID RECEPTOR LIGANDS by Katherine M
    INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS By Katherine M. Prevatt-Smith Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. _________________________________ Chairperson: Dr. Thomas E. Prisinzano _________________________________ Dr. Brian S. J. Blagg _________________________________ Dr. Michael F. Rafferty _________________________________ Dr. Paul R. Hanson _________________________________ Dr. Susan M. Lunte Date Defended: July 18, 2012 The Dissertation Committee for Katherine M. Prevatt-Smith certifies that this is the approved version of the following dissertation: INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS _________________________________ Chairperson: Dr. Thomas E. Prisinzano Date approved: July 18, 2012 ii ABSTRACT Kappa opioid (KOP) receptors have been suggested as an alternative target to the mu opioid (MOP) receptor for the treatment of pain because KOP activation is associated with fewer negative side-effects (respiratory depression, constipation, tolerance, and dependence). The KOP receptor has also been implicated in several abuse-related effects in the central nervous system (CNS). KOP ligands have been investigated as pharmacotherapies for drug abuse; KOP agonists have been shown to modulate dopamine concentrations in the CNS as well as attenuate the self-administration of cocaine in a variety of species, and KOP antagonists have potential in the treatment of relapse. One drawback of current opioid ligand investigation is that many compounds are based on the morphine scaffold and thus have similar properties, both positive and negative, to the parent molecule. Thus there is increasing need to discover new chemical scaffolds with opioid receptor activity.
    [Show full text]
  • TABLE 1 Studies of Antagonist Activity in Constitutively Active
    TABLE 1 Studies of antagonist activity in constitutively active receptors systems shown to demonstrate inverse agonism for at least one ligand Targets are natural Gs and constitutively active mutants (CAM) of GPCRs. Of 380 antagonists, 85% of the ligands demonstrate inverse agonism. Receptor Neutral Antagonist Inverse Agonist Reference Human β2-adrenergic Dichloroisoproterenol, pindolol, labetolol, timolol, Chidiac et al., 1996; Azzi et alprenolol, propranolol, ICI 118,551, cyanopindolol al., 2001 Turkey erythrocyte β-adrenergic Propranolol, pindolol Gotze et al., 1994 Human β2-adrenergic (CAM) Propranolol Betaxolol, ICI 118,551, sotalol, timolol Samama et al., 1994; Stevens and Milligan, 1998 Human/guinea pig β1-adrenergic Atenolol, propranolol Mewes et al., 1993 Human β1-adrenergic Carvedilol CGP20712A, metoprolol, bisoprolol Engelhardt et al., 2001 Rat α2D-adrenergic Rauwolscine, yohimbine, WB 4101, idazoxan, Tian et al., 1994 phentolamine, Human α2A-adrenergic Napthazoline, Rauwolscine, idazoxan, altipamezole, levomedetomidine, Jansson et al., 1998; Pauwels MPV-2088 (–)RX811059, RX 831003 et al., 2002 Human α2C-adrenergic RX821002, yohimbine Cayla et al., 1999 Human α2D-adrenergic Prazosin McCune et al., 2000 Rat α2-adrenoceptor MK912 RX821002 Murrin et al., 2000 Porcine α2A adrenoceptor (CAM- Idazoxan Rauwolscine, yohimbine, RX821002, MK912, Wade et al., 2001 T373K) phentolamine Human α2A-adrenoceptor (CAM) Dexefaroxan, (+)RX811059, (–)RX811059, RS15385, yohimbine, Pauwels et al., 2000 atipamezole fluparoxan, WB 4101 Hamster α1B-adrenergic
    [Show full text]
  • 8–21–09 Vol. 74 No. 161 Friday Aug. 21, 2009 Pages 42169–42572
    8–21–09 Friday Vol. 74 No. 161 Aug. 21, 2009 Pages 42169–42572 VerDate Nov 24 2008 21:37 Aug 20, 2009 Jkt 217001 PO 00000 Frm 00001 Fmt 4710 Sfmt 4710 E:\FR\FM\21AUWS.LOC 21AUWS srobinson on DSKHWCL6B1PROD with MISCELLANEOUS II Federal Register / Vol. 74, No. 161 / Friday, August 21, 2009 The FEDERAL REGISTER (ISSN 0097–6326) is published daily, SUBSCRIPTIONS AND COPIES Monday through Friday, except official holidays, by the Office of the Federal Register, National Archives and Records PUBLIC Administration, Washington, DC 20408, under the Federal Register Subscriptions: Act (44 U.S.C. Ch. 15) and the regulations of the Administrative Paper or fiche 202–512–1800 Committee of the Federal Register (1 CFR Ch. I). The Assistance with public subscriptions 202–512–1806 Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402 is the exclusive distributor of the official General online information 202–512–1530; 1–888–293–6498 edition. Periodicals postage is paid at Washington, DC. Single copies/back copies: The FEDERAL REGISTER provides a uniform system for making Paper or fiche 202–512–1800 available to the public regulations and legal notices issued by Assistance with public single copies 1–866–512–1800 Federal agencies. These include Presidential proclamations and (Toll-Free) Executive Orders, Federal agency documents having general FEDERAL AGENCIES applicability and legal effect, documents required to be published by act of Congress, and other Federal agency documents of public Subscriptions: interest. Paper or fiche 202–741–6005 Documents are on file for public inspection in the Office of the Assistance with Federal agency subscriptions 202–741–6005 Federal Register the day before they are published, unless the issuing agency requests earlier filing.
    [Show full text]
  • 2 Biologically Active Nucleoside Analogues with 5- Or 6- Membered Monocyclic Nucleobases 31
    VU Research Portal Robust Applications in Time-Shared Distributed Systems Dobber, A.M. 2006 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Dobber, A. M. (2006). Robust Applications in Time-Shared Distributed Systems. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 25. Sep. 2021 Mureidomycin A and Dihydropyrimidine Nucleosides Exploring efficient multicomponent reactions and chemo‐enzymatic approaches Danielle J. Vugts © 2006, D. J. Vugts, Amsterdam Cover design: Anette Coppens VRIJE UNIVERSITEIT Mureidomycin A and Dihydropyrimidine Nucleosides Exploring efficient multicomponent reactions and chemo-enzymatic approaches ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. L.M. Bouter, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Exacte Wetenschappen op vrijdag 15 december 2006 om 13.45 uur in het auditorium van de universiteit, De Boelelaan 1105 door Daniëlle Johanna Vugts geboren te Tilburg promotor: prof.dr.
    [Show full text]
  • Dynamic Regulation of Synaptic GABA Release by the Glutamate-Glutamine Cycle in Hippocampal Area CA1
    The Journal of Neuroscience, August 16, 2006 • 26(33):8537–8548 • 8537 Development/Plasticity/Repair Dynamic Regulation of Synaptic GABA Release by the Glutamate-Glutamine Cycle in Hippocampal Area CA1 Shu-Ling Liang,1 Gregory C. Carlson,1 and Douglas A. Coulter1,2 1Division of Neurology and the Pediatric Regional Epilepsy Program, Children’s Hospital of Philadelphia, and 2Departments of Pediatrics, Neurology, and Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 Vesicular GABA and intraterminal glutamate concentrations are in equilibrium, suggesting inhibitory efficacy may depend on glutamate availability. Two main intraterminal glutamate sources are uptake by neuronal glutamate transporters and glutamine synthesized through the astrocytic glutamate-glutamine cycle. We examined the involvement of the glutamate-glutamine cycle in modulating GABAergic synaptic efficacy. In the absence of neuronal activity, disruption of the glutamate-glutamine cycle by blockade of neuronal glutamine transport with ␣-(methylamino) isobutyric acid (MeAIB; 5 mM) or inhibition of glutamine synthesis in astrocytes with methionine sulfoximine (MSO; 1.5 mM) had no effect on miniature IPSCs recorded in hippocampal area CA1 pyramidal neurons. How- ever, after a period of moderate synaptic activity, application of MeAIB, MSO, or dihydrokainate (250 ␮M; an astrocytic glutamate transporter inhibitor) significantly reduced evoked IPSC (eIPSC) amplitudes. The MSO effect could be reversed by exogenous application of glutamine (5 mM), whereas glutamine could not rescue the eIPSC decreases induced by the neuronal glutamine transporter inhibitor MeAIB. The activity-dependent reduction in eIPSCs by glutamate-glutamine cycle blockers was accompanied by an enhanced blocking effect of the low-affinity GABAA receptor antagonist, TPMPA [1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid], consistent with diminished GABA release.
    [Show full text]
  • The G Protein-Coupled Glutamate Receptors As Novel Molecular Targets in Schizophrenia Treatment— a Narrative Review
    Journal of Clinical Medicine Review The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment— A Narrative Review Waldemar Kryszkowski 1 and Tomasz Boczek 2,* 1 General Psychiatric Ward, Babinski Memorial Hospital in Lodz, 91229 Lodz, Poland; [email protected] 2 Department of Molecular Neurochemistry, Medical University of Lodz, 92215 Lodz, Poland * Correspondence: [email protected] Abstract: Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology. Citation: Kryszkowski, W.; Boczek, T. The G Protein-Coupled Glutamate Keywords: schizophrenia; metabotropic glutamate receptors; positive allosteric modulators; negative Receptors as Novel Molecular Targets allosteric modulators; drug development; animal models of schizophrenia; clinical trials in Schizophrenia Treatment—A Narrative Review. J. Clin. Med. 2021, 10, 1475. https://doi.org/10.3390/ jcm10071475 1. Introduction Academic Editors: Andreas Reif, Schizophrenia is a common debilitating disease affecting about 0.3–1% of the human Blazej Misiak and Jerzy Samochowiec population worldwide [1].
    [Show full text]
  • Methionine Sulfoximine: a Novel Anti Inflammatory Agent
    Wayne State University Wayne State University Dissertations January 2018 Methionine Sulfoximine: A Novel Anti Inflammatory Agent Tyler Peters Wayne State University, [email protected] Follow this and additional works at: https://digitalcommons.wayne.edu/oa_dissertations Part of the Biochemistry Commons Recommended Citation Peters, Tyler, "Methionine Sulfoximine: A Novel Anti Inflammatory Agent" (2018). Wayne State University Dissertations. 2124. https://digitalcommons.wayne.edu/oa_dissertations/2124 This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. METHIONINE SULFOXIMINE: A NOVEL ANTI-INFLAMMATORY AGENT by TYLER J. PETERS DISSERTATION Submitted to the Graduate School of Wayne State University – School of Medicine Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOHPY 2018 MAJOR: BIOCHEMISTRY & MOL. BIOLOGY Approved By: __________________________________________ Advisor Date DEDICATION This work is dedicated to my family. I wouldn’t have made it this far without your unconditional love and support. ii ACKNOWLEDGEMENTS Thank you Dr. Brusilow, I consider myself very fortunate for having the privilege of working in the laboratory of Dr. William S.A. Brusilow these past few years. Under his mentorship, my scientific autonomy was always respected, and my opinions were always valued with consideration. I am thankful for his guidance and support as an advisor; I truly admire his patience and envy his calm demeanor. He exemplifies scientific integrity, and his dedication to develop MSO has inspired me. I had never experienced consistent failure in any aspect of life before encountering scientific research; at times I felt that Dr.
    [Show full text]
  • Endogenous Metabolites: JHU NIMH Center Page 1
    S. No. Amino Acids (AA) 24 L-Homocysteic acid 1 Glutaric acid 25 L-Kynurenine 2 Glycine 26 N-Acetyl-Aspartic acid 3 L-arginine 27 N-Acetyl-L-alanine 4 L-Aspartic acid 28 N-Acetyl-L-phenylalanine 5 L-Glutamine 29 N-Acetylneuraminic acid 6 L-Histidine 30 N-Methyl-L-lysine 7 L-Isoleucine 31 N-Methyl-L-proline 8 L-Leucine 32 NN-Dimethyl Arginine 9 L-Lysine 33 Norepinephrine 10 L-Methionine 34 Phenylacetyl-L-glutamine 11 L-Phenylalanine 35 Pyroglutamic acid 12 L-Proline 36 Sarcosine 13 L-Serine 37 Serotonin 14 L-Tryptophan 38 Stachydrine 15 L-Tyrosine 39 Taurine 40 Urea S. No. AA Metabolites and Conjugates 1 1-Methyl-L-histidine S. No. Carnitine conjugates 2 2-Methyl-N-(4-Methylphenyl)alanine 1 Acetyl-L-carnitine 3 3-Methylindole 2 Butyrylcarnitine 4 3-Methyl-L-histidine 3 Decanoyl-L-carnitine 5 4-Aminohippuric acid 4 Isovalerylcarnitine 6 5-Hydroxylysine 5 Lauroyl-L-carnitine 7 5-Hydroxymethyluracil 6 L-Glutarylcarnitine 8 Alpha-Aspartyl-lysine 7 Linoleoylcarnitine 9 Argininosuccinic acid 8 L-Propionylcarnitine 10 Betaine 9 Myristoyl-L-carnitine 11 Betonicine 10 Octanoylcarnitine 12 Carnitine 11 Oleoyl-L-carnitine 13 Creatine 12 Palmitoyl-L-carnitine 14 Creatinine 13 Stearoyl-L-carnitine 15 Dimethylglycine 16 Dopamine S. No. Krebs Cycle 17 Epinephrine 1 Aconitate 18 Hippuric acid 2 Citrate 19 Homo-L-arginine 3 Ketoglutarate 20 Hydroxykynurenine 4 Malate 21 Indolelactic acid 5 Oxalo acetate 22 L-Alloisoleucine 6 Succinate 23 L-Citrulline 24 L-Cysteine-glutathione disulfide Semi-quantitative analysis of endogenous metabolites: JHU NIMH Center Page 1 25 L-Glutathione, reduced Table 1: Semi-quantitative analysis of endogenous molecules and their derivatives by Liquid Chromatography- Mass Spectrometry (LC-TripleTOF “or” LC-QTRAP).
    [Show full text]
  • Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: a PET Study in Conscious Monkeys
    Neuropsychopharmacology (2013) 38, 2666–2674 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys 1 1 1 1 1 Shigeyuki Yamamoto , Hiroyuki Ohba , Shingo Nishiyama , Norihiro Harada , Takeharu Kakiuchi , 1 ,2 Hideo Tsukada and Edward F Domino* 1 2 Central Research Laboratory, Hamamatsu Photonics KK, Hamakita, Japan; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys 11 underwent four positron emission tomography measurements with [ C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzoni- 11 trile ([ C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a 11 dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [ C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT1A-R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [11C]DASB. No significant changes were observed in either 5-HT -R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased 1A serotonin levels in the extracellular fluid of the prefrontal cortex.
    [Show full text]
  • Activation of 5-HT2C (But Not 5-HT1A) Receptors in the Amygdala Enhances Fear-Induced Antinociception: Blockade with Local 5-HT2C Antagonist Or Systemic fluoxetine
    Neuropharmacology 135 (2018) 376e385 Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm Activation of 5-HT2C (but not 5-HT1A) receptors in the amygdala enhances fear-induced antinociception: Blockade with local 5-HT2C antagonist or systemic fluoxetine Lígia Renata Rodrigues Tavares a, b, Daniela Baptista-de-Souza a, c, * Azair Canto-de-Souza a, b, c, d, a Psychobiology Group, Department of Psychology/CECH- Federal University of Sao~ Carlos-UFSCar, Sao~ Carlos, Sao~ Paulo, 13565-905, Brazil b Joint Graduate Program in Physiological Sciences UFSCar/UNESP, Sao~ Carlos, Sao~ Paulo, 13565-905, Brazil c Neuroscience and Behavioral Institute-IneC, Ribeirao~ Preto, Sao~ Paulo, 14040-901, Brazil d Program in Psychology UFSCar, Sao~ Carlos, Sao~ Paulo, 13565-905, Brazil article info abstract Article history: It is well-known that the exposure of rodents to threatening environments [e.g., the open arm of the Received 17 August 2017 elevated-plus maze (EPM)] elicits pain inhibition. Systemic and/or intracerebral [e.g., periaqueductal gray Received in revised form matter, amygdala) injections of antiaversive drugs [e.g., serotonin (5-HT) ligands, selective serotonin 5 March 2018 reuptake inhibitors (SSRIs)] have been used to change EPM-open arm confinement induced anti- Accepted 6 March 2018 nociception (OAA). Here, we investigated (i) the role of the 5-HT and 5-HT receptors located in the Available online 13 March 2018 1A 2C amygdaloid complex on OAA as well as (ii) the effects of systemic pretreatment with fluoxetine (an SSRI) on the effects of intra-amygdala injections of 8-OH-DPAT (a 5-HT1A agonist) or MK-212 (a 5-HT2C agonist) Keywords: fi Amygdala on nociception in mice con ned to the open arm or enclosed arm of the EPM.
    [Show full text]
  • Inhibitory Role for GABA in Autoimmune Inflammation
    Inhibitory role for GABA in autoimmune inflammation Roopa Bhata,1, Robert Axtella, Ananya Mitrab, Melissa Mirandaa, Christopher Locka, Richard W. Tsienb, and Lawrence Steinmana aDepartment of Neurology and Neurological Sciences and bDepartment of Molecular and Cellular Physiology, Beckman Center for Molecular Medicine, Stanford University, Stanford, CA 94305 Contributed by Richard W. Tsien, December 31, 2009 (sent for review November 30, 2009) GABA, the principal inhibitory neurotransmitter in the adult brain, serum (13). Because actions of exogenous GABA on inflammation has a parallel inhibitory role in the immune system. We demon- and of endogenous GABA on phasic synaptic inhibition both strate that immune cells synthesize GABA and have the machinery occur at millimolar concentrations (5, 8, 9), we hypothesized that for GABA catabolism. Antigen-presenting cells (APCs) express local mechanisms may also operate in the peripheral immune functional GABA receptors and respond electrophysiologically to system to enhance GABA levels near the inflammatory focus. We GABA. Thus, the immune system harbors all of the necessary first asked whether immune cells have synthetic machinery to constituents for GABA signaling, and GABA itself may function as produce GABA by Western blotting for GAD, the principal syn- a paracrine or autocrine factor. These observations led us to ask thetic enzyme. We found significant amounts of a 65-kDa subtype fl further whether manipulation of the GABA pathway in uences an of GAD (GAD-65) in dendritic cells (DCs) and lower levels in animal model of multiple sclerosis, experimental autoimmune macrophages (Fig. 1A). GAD-65 increased when these cells were encephalomyelitis (EAE). Increasing GABAergic activity amelio- stimulated (Fig.
    [Show full text]