Target Validation Information
TTD ID T54128
Target Name Glutamate receptor AMPA (GRIA)
Type of Target
Successful
Drug Potency against Target Dihydroergotoxine Drug Info EC50 = 32400 nM [19]
Gaboxadol Drug Info IC50 = 130 nM [24]
Lindane Drug Info IC50 = 61000 nM [18]
Zopiclone Drug Info IC50 = 35.8 nM [25]
AZD6280 Drug Info IC50 = 50 nM [20]
Becampanel Drug Info IC50 = 11 nM [22]
Bicifadine Drug Info IC50 = 910 nM [11]
CX-516 Drug Info Ki = 0.3 nM [23]
Drug Info Ki = 280 nM [14]
Drug Info Ki = 40 nM [12]
(S)-AMPA Drug Info Ki = 128 nM [7]
(S)-WILLARDIINE Drug Info Ki = 8850 nM [16]
2-AMINO-3-(4-HYDROXY-1,2,5-OXADIAZOL-3-YL)PROPIONIC ACID (STRUCTURAL MIX) Drug Info Ki = 250 nM [14]
7-chloro-3-hydroxyquinazoline-2,4-dione Drug Info Ki = 11600 nM [9]
GYKI-52466 Drug Info IC50 = 12600 nM [6]
GYKI-53655 Drug Info IC50 = 1000 nM [15]
LY293558 Drug Info Ki = 2210 nM [5]
N-(4-hydroxyphenylpropanyl)-spermine Drug Info IC50 = 320 nM [13]
NBQX Drug Info IC50 = 2500 nM [10]
Piriqualone Drug Info IC50 = 460 nM [2]
RPR-118723 Drug Info IC50 = 2100 nM [1]
YM-90K Drug Info Ki = 100 nM [4]
ZK-200775 Drug Info IC50 = 140 nM [3]
Zonampanel Drug Info Ki = 62 nM [4]
[3H]CNQX Drug Info IC50 = 214 nM [8]
[3H]kainate Drug Info Ki = 3570 nM [12]
Action against Disease Model Gaboxadol Drug Info A large n uMber of the compounds showing agonist activity at the GABA(A) receptor site are structurally derived from the GABA(A) agonists muscimol, THIP (Gaboxadol), or isoguvacine, which we developed at the initial stage of the project. Using recombinant GABA(A) receptors, functional selectivity has been shown for a n uMber of compounds, including THIP, showing subunit-dependent potency and maximal response. The pharmacological and clinical activities of THIP probably reflect its potent effects at extrasynaptic GABA(A) receptors insensitive to benzodiazepines and containing alpha(4)beta(3)delta subunits. The results of ongoing clinical studies on the effect of the partial GABA(A) agonist THIP on h uMan sleep pattern show that the functional consequences of a directly acting agonist are distinctly different from those seen after administration of GABA(A) receptor modulators, such as benzodiazepines. In the light of the interest in partial GABA(A) receptor agonists as potential therapeutics, structure-activity studies of a n uMber of analogues of 4-PIOL, a low-efficacy partial GABA(A) agonist derived from THIP, have been performed. In this connection, a seriesof GABA(A) ligands has been developed showing pharmacological profiles ranging from low-efficacy partial GABA(A) agonist activity to selective antagonist effect.Rat cortical wedge preparation EC50: 1300 nM [21]
Isoflurane Drug Info Mg2+ and ketamine interact superadditively at N- methyl-D-aspartate (NMDA) receptors, which may explain the clinical efficacy of the combination. Because patients are usually exposed concomitantly to volatile anesthetics, we tested the hypothesis that volatile anesthetics interact with ketamine and/or Mg2+ at recombinantly expressed NMDA receptors. NR1/NR2A or NR1/NR2B receptors were expressed in Xenopus oocytes. We determined the effects of isoflurane, sevoflurane, and desflurane on NMDA receptor signaling, alone and in combination with S(+)-ketamine (4.1 microM on NR1/NR2A, 3.0 microM on NR2/NR2B) and/or Mg2+ (416 microM on NR1/NR2A, 629 microM on NR1/NR2B). Volatile anesthetics inhibited NR1/NR2A and NR1/NR2B glutamate receptor function in a reversible, concentration-dependent, voltage-insensitive and noncompetitive manner (half-maximal inhibitory concentration at NR1/NR2A receptors: 1.30 +/- 0.02 minim uM alveolar anesthetic concentration [MAC] for isoflurane, 1.18 +/- 0.03 MAC for desflurane, 1.24 +/- 0.06 MAC for sevoflurane; at NR1/NR2B receptors: 1.33 +/- 0.12 MAC for isoflurane, 1.22 +/- 0.08 MAC for desflurane, and 1.28 +/- 0.08 MAC for sevoflurane). On both NR1/NR2A and NR1/NR2B receptors, 50% inhibitory concentration for volatile anesthetics was reduced approximately 20% by Mg2+, approximately 30% by S(+)-ketamine, and approximately 50% by thecompounds in combination. Volatile anesthetic effects on NMDA receptors can be potentiated significantly by Mg2+, S(+)-ketamine, or-most profoundly-both. Therefore, the analgesic effects of ketamine and Mg2+, are likely to be enhanced in the presence of volatile anesthetics. IMPLICATIONS: Clinically relevant concentrations of volatile anesthetics inhibit functioning of N-methyl-D-aspartate receptors expressed recombinantly in Xenopus oocytes. This inhibition is reversible, concentration-dependent and voltage-insensitive, and results from noncompetitive antagonism of glutamate/glycine signaling. In addition, these effects can be potentiated significantly by co-application of either Mg2+, S(+)-ketamine, or--most profoundly--both. [17]
References
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REF 6 New 7,8-ethylenedioxy-2,3-benzodiazepines as noncompetitive AMPA receptor antagonists. Bioorg Med Chem Lett. 2006 Jan 1;16(1):167-70.
REF 7 Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors. J Med Chem. 2005 Dec 1;48(24):7867-81.
REF 8 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 9 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 10 Synthesis and pharmacological characterization of N3-substituted willardiine derivatives: role of the substituent at the 5-position of the uracil r... J Med Chem. 2007 Apr 5;50(7):1558-70.
REF 11 Studies on the structure-activity relationship of bicifadine analogs as monoamine transporter inhibitors. Bioorg Med Chem Lett. 2008 Jul 1;18(13):3682-6.
REF 12 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 13 Developing a complete pharmacology for AMPA receptors: a perspective on subtype-selective ligands. Bioorg Med Chem. 2010 Feb 15;18(4):1381-7.
REF 14 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological charact... J Med Chem. 2010 May 27;53(10):4110-8.
REF 15 Substituted 1,2-dihydrophthalazines: potent, selective, and noncompetitive inhibitors of the AMPA receptor. J Med Chem. 1996 Jan 19;39(2):343-6.
REF 16 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 17 Modulation of NMDA receptor function by ketamine and magnesium. Part II: interactions with volatile anesthetics. Anesth Analg. 2001 May;92(5):1182-91.
REF 18 The organochlorine pesticides gamma-hexachlorocyclohexane (lindane), alpha-endosulfan and dieldrin differentially interact with GABA(A) and glycine-gated chloride channels in primary cultures of cerebellar granule cells. Neuroscience. 2003;117(2):397-403.
REF 19 Effect of ergot alkaloids on 3H-flunitrazepam binding to mouse brain GABAA receptors. Coll Antropol. 2003;27 Suppl 1:175-82.
REF 20 HIV-1 integrase inhibitors: a decade of research and two drugs in clinical trial. Curr Top Med Chem. 2004;4(10):1059-77.
REF 21 GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic. Biochem Pharmacol. 2004 Oct 15;68(8):1573-80.
REF 22 AMPA receptor antagonists as potential anticonvulsant drugs. Curr Top Med Chem. 2005;5(1):31-42.
REF 23 Targeting DHFR in parasitic protozoa. Drug Discov Today. 2005 Jan 15;10(2):121-8.
REF 24 The role of structure activity relationship studies in the search for new GABA uptake inhibitors. Mini Rev Med Chem. 2008 Oct;8(12):1214-23.
REF 25 The effect of cyclopyrrolones on GABAA receptor function is different from that of benzodiazepines. Naunyn Schmiedebergs Arch Pharmacol. 1994 Sep;350(3):294-300.

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