22 results match your criteria mglur-1 inhibitors

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Novel thienopyrimidine analogues as potential metabotropic glutamate receptors inhibitors and anticancer activity: Synthesis, In-vitro, In-silico, and SAR approaches.

Bioorg Chem 2021 Apr 16;109:104729. Epub 2021 Feb 16.

Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Cairo, Egypt; Center of Scientific Excellence "Helwan Structural Biology Research, (HSBR)", Helwan University, Cairo 11795, Egypt.

There is a continuous need in drug development approach for synthetic anticancer analogues with new therapeutic targets to diminish chemotherapeutic resistance of cancer cells. This study presents new group of synthetic thienopyrimidine analogues (1-9) aims as mGluR-1 inhibitors with anticancer activity. In-vitro antiproliferative assessment was carried out using viability assay against cancer cell lines (MCF-7, A-549 and PC-3) compared to WI-38 normal cell line. Read More

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Brain penetration, target engagement, and disposition of the blood-brain barrier-crossing bispecific antibody antagonist of metabotropic glutamate receptor type 1.

FASEB J 2016 05 2;30(5):1927-40. Epub 2016 Feb 2.

Human Health Therapeutics Portfolio, National Research Council of Canada, Ottawa, Ontario, Canada.

Receptor mediated transcytosis harnessing the cellular uptake and transport of natural ligands across the blood-brain barrier (BBB) has been identified as a means for antibody delivery to the CNS. In this study, we characterized bispecific antibodies in which a BBB-crossing antibody fragment FC5 was used as a BBB carrier. Cargo antibodies were either a high-affinity, selective antibody antagonist of the metabotropic glutamate receptor-1 (BBB-mGluR1), a widely abundant CNS target, or an IgG that does not bind the CNS target (BBB-NiP). Read More

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Ionizing Radiation Induces Altered Neuronal Differentiation by mGluR1 through PI3K-STAT3 Signaling in C17.2 Mouse Neural Stem-Like Cells.

PLoS One 2016 1;11(2):e0147538. Epub 2016 Feb 1.

Radiation Biotechnology Research Division, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea.

Most studies of IR effects on neural cells and tissues in the brain are still focused on loss of neural stem cells. On the other hand, the effects of IR on neuronal differentiation and its implication in IR-induced brain damage are not well defined. To investigate the effects of IR on C17. Read More

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Downregulation of postsynaptic density-95-interacting regulator of spine morphogenesis reduces glutamate-induced excitotoxicity by differentially regulating glutamate receptors in rat cortical neurons.

FEBS J 2013 Dec 16;280(23):6114-27. Epub 2013 Oct 16.

Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Glutamate-induced excitotoxicity is involved in many neurological diseases. Preso, a novel postsynaptic scaffold protein, mediates excitatory synaptic transmission and various synaptic functions. In this study, we investigated the role of Preso in the regulation of glutamate-induced excitotoxicity in rat cortical neurons. Read More

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December 2013

Anxiolytic properties of Valeriana officinalis in the zebrafish: a possible role for metabotropic glutamate receptors.

Planta Med 2012 Nov 24;78(16):1719-24. Epub 2012 Aug 24.

Department of Pharmacology and Toxicology, School of Medicine, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico.

Valerian extract is used in complementary and alternative medicine for its anxiolytic and sedative properties. Our previous research demonstrated valerian interactions with glutamate receptors. The purpose of this study was to determine if valerian anxiolytic properties are mediated by metabotropic glutamate receptors (mGluR) such as mGluR (1/5) (mGluR I) and mGluR (2/3) (mGluR II). Read More

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November 2012

Pharmacological evidence of functional inhibitory metabotrophic glutamate receptors on mouse arousal-related cholinergic laterodorsal tegmental neurons.

Neuropharmacology 2013 Mar 21;66:99-113. Epub 2012 Feb 21.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitsparken 2, Copenhagen 2100, Denmark.

Cholinergic neurons of the pontine laterodorsal tegmentum (LDT) are importantly involved in neurobiological mechanisms governing states of arousal such as sleep and wakefulness as well as other appetitive behaviors, such as drug-seeking. Accordingly, mechanisms controlling their excitability are important to elucidate if we are to understand how these LDT neurons generate arousal states. Glutamate mediates the vast majority of excitatory synaptic transmission in the vertebrate CNS and while presence of glutamate input in the LDT has been shown and ionotropic responses to glutamate have been reported in the LDT, characterization of metabotropic responses is lacking. Read More

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Parasagittally aligned, mGluR1-dependent patches are evoked at long latencies by parallel fiber stimulation in the mouse cerebellar cortex in vivo.

J Neurophysiol 2011 Apr 2;105(4):1732-46. Epub 2011 Feb 2.

Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.

The parallel fibers (PFs) in the cerebellar cortex extend several millimeters along a folium in the mediolateral direction. The PFs are orthogonal to and cross several parasagittal zones defined by the olivocerebellar and corticonuclear pathways and the expression of molecular markers on Purkinje cells (PCs). The functions of these two organizations remain unclear, including whether the bands respond similarly or differentially to PF input. Read More

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Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats.

Am J Physiol Gastrointest Liver Physiol 2009 Oct 30;297(4):G781-91. Epub 2009 Jul 30.

Greater Los Angeles Veterans Affairs Healthcare System, Department of Medicine, School of Medicine, University of California, Brentwood Biomedical Research Institute, Los Angeles, California, USA.

Presence of taste receptor families in the gastrointestinal mucosa suggests a physiological basis for local and early detection of a meal. We hypothesized that luminal L-glutamate, which is the primary nutrient conferring fundamental umami or proteinaceous taste, influences mucosal defense mechanisms in rat duodenum. We perfused the duodenal mucosa of anesthetized rats with L-glutamate (0. Read More

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October 2009

Unique antipsychotic activities of the selective metabotropic glutamate receptor 1 allosteric antagonist 2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one.

J Pharmacol Exp Ther 2009 Jul 9;330(1):179-90. Epub 2009 Apr 9.

Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan.

A newly discovered metabotropic glutamate receptor (mGluR) 1 allosteric antagonist, 2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one (CFMTI), was tested both in vitro and in vivo for its pharmacological effects. CFMTI demonstrated potent and selective antagonistic activity on mGluR1 in vitro and in vivo after oral administration. CFMTI inhibited L-glutamate-induced intracellular Ca(2+) mobilization in Chinese hamster ovary cells expressing human and rat mGluR1a, with IC(50) values of 2. Read More

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The potent non-competitive mGlu1 receptor antagonist BAY 36-7620 differentially affects synaptic plasticity in area cornu ammonis 1 of rat hippocampal slices and impairs acquisition in the water maze task in mice.

Neuroscience 2008 Nov 9;157(2):385-95. Epub 2008 Sep 9.

Research Institute for Applied Neurosciences GmbH, Leipziger Str. 44, D-39120 Magdeburg, Germany.

In this study we evaluated the effects of the novel, potent non-competitive metabotropic glutamate receptor (mGluR) 1 antagonist (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-on (BAY 36-7620) on different types of synaptic plasticity in the hippocampal cornu ammonis (CA) 1-region and on hippocampus-dependent spatial learning. After having confirmed the presence of mGluR1 in the hippocampal CA1 region of our rat strain by confocal microscopy, we tested the effects of BAY 36-7620 on: 1) long-term potentiation (LTP) induced by weak and strong stimulation; 2) 3,5-dihydroxyphenylglycine (DHPG, 30 microM)-induced depression of synaptic transmission; and 3) learning of the hidden platform version of the water maze by mice. BAY 36-7620 (10 microM) amplified LTP but, like the mGluR1 antagonists 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt, 10 microM) and 4-carboxyphenylglycine (4-CPG, 50 microM), diminished LTP at 1 microM. Read More

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November 2008

Pharmacological effects of the metabotropic glutamate receptor 1 antagonist compared with those of the metabotropic glutamate receptor 5 antagonist and metabotropic glutamate receptor 2/3 agonist in rodents: detailed investigations with a selective allosteric metabotropic glutamate receptor 1 antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide].

J Pharmacol Exp Ther 2008 Aug 16;326(2):577-86. Epub 2008 May 16.

Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan.

The functional roles of metabotropic glutamate receptor (mGluR) 1 in integrative brain functions were investigated using a potent and selective mGluR1 allosteric antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide], in comparison with the mGluR5 allosteric antagonist and the mGluR2/3 orthosteric agonist in rodents. FTIDC reduced maternal separation-induced ultrasonic vocalization and stress-induced hyperthermia without affecting behaviors in the elevated plus maze. An mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and an mGluR2/3 agonist, LY379268 [(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3. Read More

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Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models.

Brain Res 2008 Jan 28;1191:168-79. Epub 2007 Nov 28.

Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, 305-8585, Japan.

We describe in vitro properties and in vivo neuroprotective effects of a newly synthesized, high-affinity, selective allosteric metabotropic glutamate receptor type 1 (mGluR(1)) antagonist, N-cyclohexyl-6-{[(2-methoxyethyl)(methyl)amino]methyl}-N-methylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-202074). YM-202074 bound an allosteric site of rat mGluR(1) with a K(i) value of 4.8+/-0. Read More

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January 2008

Pharmacological characterization of a new, orally active and potent allosteric metabotropic glutamate receptor 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC).

J Pharmacol Exp Ther 2007 Jun 14;321(3):1144-53. Epub 2007 Mar 14.

Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan.

A highly potent and selective metabotropic glutamate receptor (mGluR) 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2, 3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC), is described. FTIDC inhibits, with equal potency, l-glutamate-induced intracellular Ca(2+) mobilization in Chinese hamster ovary cells expressing human, rat, or mouse mGluR1a. The IC(50) value of FTIDC is 5. Read More

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Peripheral metabotropic glutamate receptor 5 mediates mechanical hypersensitivity in craniofacial muscle via protein kinase C dependent mechanisms.

Authors:
J-S Lee J Y Ro

Neuroscience 2007 Apr 15;146(1):375-83. Epub 2007 Feb 15.

Department of Biomedical Sciences, Program in Neuroscience, University of Maryland Baltimore School of Dentistry, 650 West Baltimore Street, Baltimore, MD 21201, USA.

We previously demonstrated that peripherally located N-methyl-D-aspartic acid (NMDA) receptors contribute to acute muscle nociception and the development of chronic muscular hyperalgesia. In the present study, we investigated the potential role of peripheral group I metabotropic glutamate receptors (mGluRs 1/5) in the development of muscular hypersensitivity to mechanical stimulation, and attempted to elucidate intracellular signaling mechanisms associated with the mGluR activation in male Sprague-Dawley rats. First, our Western blot analyses revealed that mGluR 5 protein, but not mGluR 1 protein, is reliably detected in trigeminal ganglia and the masseter nerve. Read More

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Metabotropic glutamate receptors differentially regulate GABAergic inhibition in thalamus.

J Neurosci 2006 Dec;26(52):13443-53

Department of Molecular and Integrative Physiology, Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana, Illinois 61801, USA.

Thalamic interneurons and thalamic reticular nucleus (TRN) neurons provide inhibitory innervation of thalamocortical cells that significantly influence thalamic gating. The local interneurons in the dorsal lateral geniculate nucleus (dLGN) give rise to two distinct synaptic outputs: classical axonal and dendrodendritic. Activation of metabotropic glutamate receptors (mGluRs) by agonists or optic tract stimulation increases the output of these presynaptic dendrites leading to increased inhibition of thalamocortical neurons. Read More

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December 2006

Axon-glia communication evokes calcium signaling in olfactory ensheathing cells of the developing olfactory bulb.

Glia 2007 Mar;55(4):352-9

Abteilung für Allgemeine Zoologie, Technische Universität Kaiserslautern, Postfach 3049, 67653 Kaiserslautern, Germany.

Olfactory ensheathing cells (OECs) accompany receptor axons in the olfactory nerve and promote axonal growth into the central nervous system. The mechanisms underlying the communication between axons and OECs, however, have not been studied in detail yet. We investigated the effect of activity-dependent neuronal transmitter release on Ca(2+) signaling of OECs in acute mouse olfactory bulb slices using confocal Ca(2+) imaging. Read More

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Optical imaging of long-term depression in the mouse cerebellar cortex in vivo.

J Neurosci 2003 Mar;23(5):1859-66

Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Conjunctive stimulation of climbing fiber and parallel fiber inputs results in long-term depression (LTD) at parallel fiber-Purkinje cell synapses. Although hypothesized to play a major role in cerebellar motor learning, there has been no characterization of the cellular and molecular mechanisms of LTD in the whole animal, let alone its spatial properties, both of which are critical to understanding the role of LTD in cerebellar function. Neutral red optical imaging of the cerebellar cortex in the anesthetized mouse was used to visualize the spatial patterns of activation. Read More

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Group I metabotropic glutamate receptors activate burst firing in rat midbrain dopaminergic neurons.

Neuropharmacology 2002 Mar;42(3):289-96

IRCCS Fondazione S. Lucia, Experimental Neurology Laboratory, Via Ardeatina 306, 00179 Rome, Italy.

We have investigated the changes in the spontaneous firing pattern induced by DHPG ((S)-3,5-dihydroxyphenylglycine) and NMDA (N-methyl-d-aspartic acid) on rat dopaminergic neurons in substantia nigra pars compacta (SNc) using sharp microelectrode recordings in in vitro conditions. Twenty-five out of 33 cells modified the regular single-pacemaker activity in burst firing when exposed to the Group I metabotropic glutamate receptor (mGluR) agonist DHPG (30 microM) and d-tubocurarine (500 microM) (d-TC), whereas they all fired in bursts during NMDA (20 microM) plus d-TC application. The blockade of SK-channels by d-TC and apamin was essential for the production of both types of bursts. Read More

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Characterization of the mGluR(1)-mediated electrical and calcium signaling in Purkinje cells of mouse cerebellar slices.

J Neurophysiol 2001 Sep;86(3):1389-97

Laboratory for Neuronal Circuit Dynamics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.

The metabotropic glutamate receptor 1 (mGluR(1)) plays a fundamental role in postnatal development and plasticity of ionotropic glutamate receptor-mediated synaptic excitation of cerebellar Purkinje cells. Synaptic activation of mGluR(1) by brief tetanic stimulation of parallel fibers evokes a slow excitatory postsynaptic current and an elevation of intracellular calcium concentration ([Ca2+](i)) in Purkinje cells. The mechanism underlying these responses has not been identified yet. Read More

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September 2001

Neuroprotection by group I metabotropic glutamate receptor antagonists in forebrain ischemia of gerbil.

Neurosci Lett 2000 Oct;293(1):1-4

Department of Neurological Surgery, Clinical Science Center, University of Wisconsin, Veterans Administration Hospital, Madison 53792, USA.

Stimulation of group I metabotropic glutamate receptors (mGluR 1 and 5) activates G-protein coupled-phospholipase C (PLC) to release 1,2-diacylglycerol (DAG) and arachidonic acid (ArAc). To elucidate the role of group I mGluR, we tested the effects of (S)-alpha-methyl-4-carboxy-phenylglycine (MCPG, mGluR 1 and 5 antagonist), 1-aminoindan-1,5-dicarboxylic acid (AIDA, mGluR 1a specific antagonist) and 2-methyl-6-(phenylethynyl) pyridine (MPEP, mGluR 5 antagonist) on ArAc release and neuronal survival after transient forebrain ischemia in gerbils. Ischemia resulted in (a) significant release of ArAc at 1-day reperfusion and (b) significant neuronal death in the hippocampal CA1 subfield after 6-day reperfusion. Read More

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October 2000

Involvement of mGluR(5) on acute nociceptive transmission.

Authors:
F Bordi A Ugolini

Brain Res 2000 Jul;871(2):223-33

Pharmacology Department, GlaxoWellcome Medicine Research Centre, Via Fleming 4, 37100, Verona, Italy.

The effect of the mGluR(5) antagonist, MPEP (2-Methyl-6-(phenylethynyl)-pyridine), and of the mGluR(1) antagonist, AIDA((RS)-1-Aminoindan-1,5-dicarboxylic acid), were examined on nociceptive neurons in the ventroposterolateral (VPL) nucleus of the thalamus in response to pressure stimuli to the contralateral hindpaw of rats under urethane anesthesia. Intravenous (i.v. Read More

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Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors.

Proc Natl Acad Sci U S A 1995 Aug;92(17):8083-7

Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge 02139, USA.

Stimulation of muscarinic m1 or m3 receptors can, by generating diacylglycerol and activating protein kinase C, accelerate the breakdown of the amyloid precursor protein (APP) to form soluble, nonamyloidogenic derivatives (APPs), as previously shown. This relationship has been demonstrated in human glioma and neuroblastoma cells, as well as in transfected human embryonic kidney 293 cells and PC-12 cells. We now provide evidence that stimulation of metabotropic glutamate receptors (mGluRs), which also are coupled to phosphatidylinositol 4,5-bisphosphate hydrolysis, similarly accelerates processing of APP into nonamyloidogenic APPs. Read More

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