Target Validation Information
Target ID T33584
Target Name Glutamate receptor 1
Target Type
Clinical Trial
Drug Potency against Target (S)-AMPA Drug Info Ki = 128 nM [527890]
(R,S)-AMPA Drug Info Ki = 21.9 nM [529714]
YM-90K Drug Info Ki = 100 nM [527219]
ZONAMPANEL Drug Info Ki = 62 nM [527219]
LY293558 Drug Info IC50 = 600 nM [525786]
N-(4-hydroxyphenylpropanyl)-spermine Drug Info IC50 = 460 nM [530651]
NBQX Drug Info IC50 = 200 nM [528453]
GLUTAMATE Drug Info Ki = 169 nM [529714]
RPR-118723 Drug Info IC50 = 2100 nM [525816]
Farampator Drug Info IC50 < 500 nM [552657]
KAINATE Drug Info Ki = 477 nM [529714]
GYKI-53655 Drug Info IC50 = 1000 nM [534085]
7-chloro-3-hydroxyquinazoline-2,4-dione Drug Info Ki = 11600 nM [528453]
Philanthotoxin-343 Drug Info IC50 = 2800 nM [530651]
Argiotoxin-636 Drug Info IC50 = 3400 nM [530651]
GYKI-52466 Drug Info IC50 = 12600 nM [527792]
(S)-WILLARDIINE Drug Info Ki = 386 nM [534502]
6-cyano-7-nitroquinoxaline-2,3-dione Drug Info IC50 = 214 nM [528135]
Piriqualone Drug Info IC50 = 460 nM [525977]
Action against Disease Model Farampator C57BL/6J mice received Org 26576 (0.1, 1, 10 mg/kg i.p.) or Org 24448 (3, 10, 30 mg/kg i.p.) or vehicle and LCGU was assessed using 14C-2-deoxyglucose autoradiography. Both compounds produced dose-dependent increases in LCGU with specific regional activation at low doses. Org 26576 (1 mg/kg) produced significant increases in 9 of the 43 areas examined, including the anteroventral and laterodorsal thalamus, cingulate cortex, dentate gyrus and CA3 subfield of the hippocampus. Org 24448 (3 mg/kg) produced significant increases in LCGU in 4 of the 43 regions examined, including the dorsal raphe nucleus, medial lateral habenula, CA1 subfield of the hippocampus and median forebrain bundle. Furthermore, the increases in LCGU observed with both Org 26576 (10 mg/kg) and Org 24448 (10 mg/kg) were blocked by pre-treatment with the AMPA receptor antagonist NBQX (10 mg/kg). These data demonstrate that both Org 26576 and Org 24448 produce dose-dependent AMPA receptor mediated increases in LCGU and provide an anatomical basis suggestive that these drugs may be of use in the treatment of conditions such as depression or schizophrenia [552536] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations GluA1 knockout (KO) mice display schizophrenia- and depression-related abnormalities. Here, we asked whether GluA1 KO show mania-related abnormalities. KO were tested for behavior in approach/avoid conflict tests, responses to repeated forced swim exposure, and locomotor responses under stress and after psychostimulant treatment. The effects of rapid dopamine depletion and treatment with lithi uM or a GSK-3-beta inhibitor (SB216763) on KO locomotor hyperactivity were tested. Results showed that KO exhibited novelty- and stress-induced locomotor hyperactivity, reduced forced swim immobility and alterations in approach/avoid conflict tests. Psychostimulant treatment and dopamine depletion exacerbated KO locomotor hyperactivity. Lithi uM, but not SB216763, treatment normalized KO anxiety-related behavior and partially reversed hyperlocomotor behavior, and also reversed elevated prefrontal cortex levels of phospho-MARCKS and phospho-neuromodulin. Collectively, these findings demonstrate mania-related abnormalities in GluA1 KO and, combined with previous findings, suggest this mutant may provide a novel model of features of schizoaffective disorder. [527890]
References
Ref 527890J Med Chem. 2005 Dec 1;48(24):7867-81.Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors.
Ref 529714J Med Chem. 2008 Oct 23;51(20):6614-8. Epub 2008 Sep 24.1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and Selective iGluR5 modulators.
Ref 527219Bioorg Med Chem Lett. 2004 Oct 18;14(20):5107-11.Synthesis and AMPA receptor antagonistic activity of a novel 7-imidazolyl-6-trifluoromethyl quinoxalinecarboxylic acid with a substituted phenyl groupand improved its good physicochemical properties by introduced CF3 group.
Ref 527219Bioorg Med Chem Lett. 2004 Oct 18;14(20):5107-11.Synthesis and AMPA receptor antagonistic activity of a novel 7-imidazolyl-6-trifluoromethyl quinoxalinecarboxylic acid with a substituted phenyl groupand improved its good physicochemical properties by introduced CF3 group.
Ref 525786Bioorg Med Chem Lett. 2000 May 15;10(10):1133-7.4,10-Dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives: highly potent and selective AMPA receptors antagonists with in vivo activity.
Ref 530651Bioorg Med Chem. 2010 Feb 15;18(4):1381-7. Epub 2010 Jan 6.Developing a complete pharmacology for AMPA receptors: a perspective on subtype-selective ligands.
Ref 528453J Med Chem. 2006 Oct 5;49(20):6015-26.Structural investigation of the 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione scaffold to obtain AMPA and kainate receptor selective antagonists. Synthesis, pharmacological, and molecular modeling studies.
Ref 529714J Med Chem. 2008 Oct 23;51(20):6614-8. Epub 2008 Sep 24.1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and Selective iGluR5 modulators.
Ref 525816J Med Chem. 2000 Jun 15;43(12):2371-81.Indeno[1,2-b]pyrazin-2,3-diones: a new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity.
Ref 552657Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers. Neuropsychopharmacology. 2007 Jun;32(6):1272-83. Epub 2006 Nov 22.
Ref 529714J Med Chem. 2008 Oct 23;51(20):6614-8. Epub 2008 Sep 24.1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and Selective iGluR5 modulators.
Ref 552536Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography. Neuropharmacology. 2005 Aug;49(2):254-64.
Ref 534085J Med Chem. 1996 Jan 19;39(2):343-6.Substituted 1,2-dihydrophthalazines: potent, selective, and noncompetitive inhibitors of the AMPA receptor.
Ref 528453J Med Chem. 2006 Oct 5;49(20):6015-26.Structural investigation of the 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione scaffold to obtain AMPA and kainate receptor selective antagonists. Synthesis, pharmacological, and molecular modeling studies.
Ref 530651Bioorg Med Chem. 2010 Feb 15;18(4):1381-7. Epub 2010 Jan 6.Developing a complete pharmacology for AMPA receptors: a perspective on subtype-selective ligands.
Ref 530651Bioorg Med Chem. 2010 Feb 15;18(4):1381-7. Epub 2010 Jan 6.Developing a complete pharmacology for AMPA receptors: a perspective on subtype-selective ligands.
Ref 527792Bioorg Med Chem Lett. 2006 Jan 1;16(1):167-70. Epub 2005 Oct 10.New 7,8-ethylenedioxy-2,3-benzodiazepines as noncompetitive AMPA receptor antagonists.
Ref 534502J Med Chem. 1997 Oct 24;40(22):3645-50.Synthesis of willardiine and 6-azawillardiine analogs: pharmacological characterization on cloned homomeric human AMPA and kainate receptor subtypes.
Ref 528135J Med Chem. 2006 Apr 20;49(8):2579-92.Structure-activity relationship studies on N3-substituted willardiine derivatives acting as AMPA or kainate receptor antagonists.
Ref 525977Bioorg Med Chem Lett. 2001 Jan 22;11(2):177-81.Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists.

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