(Rac)-NMDAR antagonist 1
目录号 : GC60413(Rac)-NMDARantagonist1是NMDARantagonist1的消旋体。NMDARantagonist1是一种有效且口服生物可利用的,NR2B选择性的NMDAR拮抗剂。
Cas No.:2435557-99-4
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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(Rac)-NMDAR antagonist 1 is the racemate of NMDAR antagonist 1. NMDAR antagonist 1 is a potent and orally bioavailable NR2B-selective NMDAR antagonist[1].
[1]. Zhang L, et al. Design, synthesis and bioevaluation of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives as potent neuroprotective agents. Eur J Med Chem. 2018 May 10;151:27-38.
Cas No. | 2435557-99-4 | SDF | |
Canonical SMILES | O=C(NCCC1=CC=C(O)C=C1)C2CCC3=NC4=CC=C(Br)C=C4CN32 | ||
分子式 | C20H20BrN3O2 | 分子量 | 414.3 |
溶解度 | DMSO: 5 mg/mL (12.07 mM); Water: < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效。 储备液的保存方式和期限:-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。 为了提高溶解度,请将管子加热至37℃,然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.4137 mL | 12.0685 mL | 24.1371 mL |
5 mM | 0.4827 mL | 2.4137 mL | 4.8274 mL |
10 mM | 0.2414 mL | 1.2069 mL | 2.4137 mL |
第一步:请输入基本实验信息(考虑到实验过程中的损耗,建议多配一只动物的药量) | ||||||||||
给药剂量 | mg/kg | 动物平均体重 | g | 每只动物给药体积 | ul | 动物数量 | 只 | |||
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% DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度: mg/ml;
DMSO母液配制方法: mg 药物溶于 μL DMSO溶液(母液浓度 mg/mL,
体内配方配制方法:取 μL DMSO母液,加入 μL PEG300,混匀澄清后加入μL Tween 80,混匀澄清后加入 μL saline,混匀澄清。
1. 首先保证母液是澄清的;
2.
一定要按照顺序依次将溶剂加入,进行下一步操作之前必须保证上一步操作得到的是澄清的溶液,可采用涡旋、超声或水浴加热等物理方法助溶。
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Calcium Signaling and Gene Expression
Adv Exp Med Biol 2020;1131:537-545.PMID:31646525DOI:10.1007/978-3-030-12457-1_22.
Calcium signaling plays an important role in gene expression. At the transcriptional level, this may underpin mammalian neuronal synaptic plasticity. Calcium influx into the postsynaptic neuron via: N-methyl-D-aspartate (NMDA) receptors activates small GTPase Rac1 and other Rac guanine nucleotide exchange factors, and stimulates calmodulin-dependent kinase kinase (CaMKK) and CaMKI; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors that are not impermeable to calcium ions, that is, those lacking the glutamate receptor-2 subunits, leads to activation of Ras guanine nucleotide-releasing factor proteins, which is coupled with activation of the mitogen-activated protein kinases/extracellular signal-regulated kinases signaling cascade; L-type voltage-gated calcium channels activates signaling pathways involving CaMKII, downstream responsive element antagonist modulator and distinct microdomains. Key members of these signaling cascades then translocate into the nucleus, where they alter the expression of genes involved in neuronal synaptic plasticity. At the post-transcriptional level, intracellular calcium level changes can change alternative splicing patterns; in the mammalian brain, alterations in calcium signaling via NMDA receptors is associated with exon silencing of the CI cassette of the NMDA R1 receptor (GRIN1) transcript by UAGG motifs in response to neuronal excitation. Regulation also occurs at the translational level; transglutaminase-2 (TG2) mediates calcium ion-regulated crosslinking of Y-box binding protein-1 (YB-1) translation-regulatory protein in TGFβ1-activated myofibroblasts; YB-1 binds smooth muscle α-actin mRNA and regulates its translational activity. Calcium signaling is also important in epigenetic regulation, for example in respect of changes in cytosine bases. Targeting calcium signaling may provide therapeutically useful options, for example to induce epigenetic reactivation of tumor suppressor genes in cancer patients.
Role of NMDA, opioid and dopamine D1 and D2 receptor signaling in the acquisition of a quinine-conditioned flavor avoidance in rats
Physiol Behav 2014 Apr 10;128:133-40.PMID:24508751DOI:10.1016/j.physbeh.2014.01.014.
A conditioned flavor preference (CFP) can be produced by pairing a flavor (conditioned stimulus, CS+) with the sweet taste of fructose. Systemic dopamine (DA) D1, D2 and NMDA, but not opioid, receptor antagonists significantly reduce the acquisition of the fructose-CFP. A conditioned flavor avoidance (CFA) can be produced by pairing a CS+flavor with the bitter taste of quinine. To evaluate whether fructose-CFP and quinine-CFA share common neurochemical substrates, the present study determined the systemic effects of DA D1 (SCH23390: SCH), DA D2 (raclopride: Rac), NMDA (MK-801) or opioid (naltrexone: NTX) receptor antagonists on the acquisition of quinine-CFA. In Experiment 1, food-restricted male rats were trained over 8 alternating one-bottle sessions to drink an 8% fructose+0.2% saccharin solution (FS) mixed with one flavor (CS-, e.g., grape) and a different flavor (CS+, e.g., cherry) mixed in a solution (FSQ) containing fructose+saccharin and quinine at 0.001-0.030% concentrations. In six subsequent two-bottle choice tests (1-3: two sessions each) with the CS- and CS+ flavors presented in FS solutions, only rats trained with 0.03% quinine displayed a CS+ avoidance in Test 1. In Experiment 2, rats received vehicle (Veh), SCH (200 nmol/kg), Rac (200 nmol/kg), MK-801 (100 μg/kg) or NTX (1 mg/kg) 30 min prior to the 8 one-bottle training sessions with CS-/FS and CS+/FSQ (0.03% quinine) solutions. An additional vehicle group (Veh 0.06%) was trained with a CS+/FSQ containing 0.06% quinine. In the two-bottle choice tests, the Veh and Rac groups avoided the CS+ flavor in Test 1 only, whereas the SCH, MK801, and NTX groups significantly avoided the CS+ in Tests 1-3. The Veh.06% group trained avoided the CS+ in Tests 1 and 2, but not Test 3. In Experiment 3, Veh and SCH groups were trained as in Experiment 2, but were tested with CS flavors presented in 0.2% saccharin solutions. The SCH group avoided the CS+ flavor in Tests 1-3 while the Veh group avoided the CS+ in Test 1 only. Thus whereas DA D1, DA D2 and NMDA, but not opioid receptor antagonism blocked acquisition of sweet taste-based CFP, DA D1, NMDA and opioid, but not DA D2 receptor antagonism enhanced the CFA produced by the bitter taste of quinine.
Kalirin binds the NR2B subunit of the NMDA receptor, altering its synaptic localization and function
J Neurosci 2011 Aug 31;31(35):12554-65.PMID:21880917DOI:10.1523/JNEUROSCI.3143-11.2011.
The ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins, including PSD-95, DISC-1, AF-6, and Arf6. Mice genetically lacking Kal7 (Kal7(KO)) exhibit deficient hippocampal long-term potentiation (LTP) as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7(KO) mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7(KO) animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7(KO) mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity.
Long-term potentiation-dependent spine enlargement requires synaptic Ca2+-permeable AMPA receptors recruited by CaM-kinase I
J Neurosci 2010 Sep 1;30(35):11565-75.PMID:20810878DOI:10.1523/JNEUROSCI.1746-10.2010.
It is well established that long-term potentiation (LTP), a paradigm for learning and memory, results in a stable enlargement of potentiated spines associated with recruitment of additional GluA1-containing AMPA receptors (AMPARs). Although regulation of the actin cytoskeleton is involved, the detailed signaling mechanisms responsible for this spine expansion are unclear. Here, we used cultured mature hippocampal neurons stimulated with a glycine-induced, synapse-specific form of chemical LTP (GI-LTP). We report that the stable structural plasticity (i.e., spine head enlargement and spine length shortening) that accompanies GI-LTP was blocked by inhibitors of NMDA receptors (NMDARs; APV) or CaM-kinase kinase (STO-609), the upstream activator of CaM-kinase I (CaMKI), as well as by transfection with dominant-negative (dn) CaMKI but not dnCaMKIV. Recruitment of GluA1 to the spine surface occurred after GI-LTP and was mimicked by transfection with constitutively active CaMKI. Spine enlargement induced by transfection of GluA1 was associated with synaptic recruitment of Ca(2+)-permeable AMPARs (CP-AMPARs) as assessed by an increase in the rectification index of miniature EPSCs (mEPSCs) and their sensitivity to IEM-1460, a selective antagonist of CP-AMPARs. Furthermore, the increase in spine size and mEPSC amplitude resulting from GI-LTP itself was blocked by IEM-1460, demonstrating involvement of CP-AMPARs. Downstream signaling effectors of CP-AMPARs, identified by suppression of their activation by IEM-1460, included the Rac/PAK/LIM-kinase pathway that regulates spine actin dynamics. Together, our results suggest that synaptic recruitment of CP-AMPARs via CaMKI may provide a mechanistic link between NMDAR activation in LTP and regulation of a signaling pathway that drives spine enlargement via actin polymerization.
Acquisition of contextual discrimination involves the appearance of a RAS-GRF1/p38 mitogen-activated protein (MAP) kinase-mediated signaling pathway that promotes long term potentiation (LTP)
J Biol Chem 2013 Jul 26;288(30):21703-13.PMID:23766509DOI:10.1074/jbc.M113.471904.
RAS-GRF1 is a guanine nucleotide exchange factor with the ability to activate RAS and Rac GTPases in response to elevated calcium levels. We previously showed that beginning at 1 month of age, RAS-GRF1 mediates NMDA-type glutamate receptor (NMDAR)-induction of long term depression in the CA1 region of the hippocampus of mice. Here we show that beginning at 2 months of age, when mice first acquire the ability to discriminate between closely related contexts, RAS-GRF1 begins to contribute to the induction of long term potentiation (LTP) in the CA1 hippocampus by mediating the action of calcium-permeable, AMPA-type glutamate receptors (CP-AMPARs). Surprisingly, LTP induction by CP-AMPARs through RAS-GRF1 occurs via activation of p38 MAP kinase rather than ERK MAP kinase, which has more frequently been linked to LTP. Moreover, contextual discrimination is blocked by knockdown of Ras-Grf1 expression specifically in the CA1 hippocampus, infusion of a p38 MAP kinase inhibitor into the CA1 hippocampus, or the injection of an inhibitor of CP-AMPARs. These findings implicate the CA1 hippocampus in the developmentally dependent capacity to distinguish closely related contexts through the appearance of a novel LTP-supporting signaling pathway.