Target Validation Information
TTD ID	T33584
Target Name	Glutamate receptor AMPA 1 (GRIA1)
Type of Target	Successful
Drug Potency against Target	Farampator	Drug Info	IC50 < 500 nM	[14]
		Drug Info	Ki = 21.9 nM	[9]
		Drug Info	Ki = 169 nM	[9]
	(S)-AMPA	Drug Info	Ki = 128 nM	[6]
	(S)-WILLARDIINE	Drug Info	Ki = 386 nM	[12]
	7-chloro-3-hydroxyquinazoline-2,4-dione	Drug Info	Ki = 11600 nM	[8]
	Argiotoxin-636	Drug Info	IC50 = 3400 nM	[10]
	GYKI-52466	Drug Info	IC50 = 12600 nM	[5]
	GYKI-53655	Drug Info	IC50 = 1000 nM	[11]
	LY293558	Drug Info	IC50 = 600 nM	[1]
	N-(4-hydroxyphenylpropanyl)-spermine	Drug Info	IC50 = 460 nM	[10]
	NBQX	Drug Info	IC50 = 200 nM	[8]
	Philanthotoxin-343	Drug Info	IC50 = 2800 nM	[10]
	Piriqualone	Drug Info	IC50 = 460 nM	[3]
	RPR-118723	Drug Info	IC50 = 2100 nM	[2]
	YM-90K	Drug Info	Ki = 100 nM	[4]
	Zonampanel	Drug Info	Ki = 62 nM	[4]
	[3H]CNQX	Drug Info	IC50 = 214 nM	[7]
	[3H]kainate	Drug Info	Ki = 477 nM	[9]
Action against Disease Model	Farampator	Drug Info	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	[13]
References
REF 1	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... Bioorg Med Chem Lett. 2000 May 15;10(10):1133-7.
REF 2	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. J Med Chem. 2000 Jun 15;43(12):2371-81.
REF 3	Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antag... Bioorg Med Chem Lett. 2001 Jan 22;11(2):177-81.
REF 4	Synthesis and AMPA receptor antagonistic activity of a novel 7-imidazolyl-6-trifluoromethyl quinoxalinecarboxylic acid with a substituted phenyl gr... Bioorg Med Chem Lett. 2004 Oct 18;14(20):5107-11.
REF 5	New 7,8-ethylenedioxy-2,3-benzodiazepines as noncompetitive AMPA receptor antagonists. Bioorg Med Chem Lett. 2006 Jan 1;16(1):167-70.
REF 6	Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors. J Med Chem. 2005 Dec 1;48(24):7867-81.
REF 7	Structure-activity relationship studies on N3-substituted willardiine derivatives acting as AMPA or kainate receptor antagonists. J Med Chem. 2006 Apr 20;49(8):2579-92.
REF 8	Structural investigation of the 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione scaffold to obtain AMPA and kainate receptor selective antagonists. Syn... J Med Chem. 2006 Oct 5;49(20):6015-26.
REF 9	1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of pot... J Med Chem. 2008 Oct 23;51(20):6614-8.
REF 10	Developing a complete pharmacology for AMPA receptors: a perspective on subtype-selective ligands. Bioorg Med Chem. 2010 Feb 15;18(4):1381-7.
REF 11	Substituted 1,2-dihydrophthalazines: potent, selective, and noncompetitive inhibitors of the AMPA receptor. J Med Chem. 1996 Jan 19;39(2):343-6.
REF 12	Synthesis of willardiine and 6-azawillardiine analogs: pharmacological characterization on cloned homomeric human AMPA and kainate receptor subtypes. J Med Chem. 1997 Oct 24;40(22):3645-50.
REF 13	Regionally 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 14	Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers. Neuropsychopharmacology. 2007 Jun;32(6):1272-83.

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