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635318-11-5 分子结构
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(1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid

ChemBase编号:73076
分子式:C7H9NO6S
平均质量:235.21446
单一同位素质量:235.01505801
SMILES和InChIs

SMILES:
[C@H]12[C@@H]([C@](CS1(=O)=O)(N)C(=O)O)[C@H]2C(=O)O
Canonical SMILES:
OC(=O)[C@@H]1[C@H]2[C@H]1S(=O)(=O)C[C@@]2(N)C(=O)O
InChI:
InChI=1S/C7H9NO6S/c8-7(6(11)12)1-15(13,14)4-2(3(4)7)5(9)10/h2-4H,1,8H2,(H,9,10)(H,11,12)/t2-,3-,4+,7+/m1/s1
InChIKey:
AVDUGNCTZRCAHH-MDASVERJSA-N

引用这个纪录

CBID:73076 http://www.chembase.cn/molecule-73076.html

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名称和登记号

名称和登记号

名称 登记号
IUPAC标准名
(1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid
IUPAC传统名
(1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid
别名
LY404039
LY2140023(LY404039)
CAS号
635318-11-5
PubChem SID
162037996
PubChem CID
9834591

数据来源

数据来源

所有数据来源 商品来源 非商品来源
数据来源 数据ID 价格
Selleck Chemicals
S6001 external link 加入购物车 请登录
数据来源 数据ID
PubChem 9834591 external link

理论计算性质

理论计算性质

JChem
Acid pKa 1.1249534  质子受体
质子供体 LogD (pH = 5.5) -6.910639 
LogD (pH = 7.4) -8.289731  Log P -4.8649364 
摩尔折射率 44.9521 cm3 极化性 19.282328 Å3
极化表面积 134.76 Å2 可自由旋转的化学键
里宾斯基五规则 true 

分子性质

分子性质

理化性质 安全信息 药理学性质 产品相关信息 生物活性(PubChem)
溶解度
DMSO expand 查看数据来源
保存条件
-20°C expand 查看数据来源
作用靶点
mGluR expand 查看数据来源
成盐信息
Free Base expand 查看数据来源

详细说明

详细说明

Selleck Chemicals Selleck Chemicals
Selleck Chemicals -  S6001 external link
Research Area
Description Neurological Disease
Biological Activity
Description LY404039 is a potent agonist of recombinant human mGlu2, mGlu3 receptors and rat neurons expressing native mGlu2/3 receptors with Ki of 149 nM, 92 nM and 88 nM, respectively.
Targets Recombinant human mGlu2 Recombinant human mGlu3 Rat neurons expressing native mGlu2/3
IC50 149 nM (Ki) 92 nM (Ki) 88 nM (Ki) [1]
In Vitro LY404039 exhibits low binding affinity to group III mGlu receptors including mGlu6, mGlu7 and mGlu8 with a Ki value more than 5 μM. LY404039 shows little affinity for ionotropic glutamate receptors, glutamate transporter subtypes, monoamine and other receptors. LY404039 potently inhibits forskolin-stimulated cAMP formation in cells expressing human mGlu2 and mGlu3 receptors. LY404039 suppresses electrically evoked excitatory activity in the striatum, and serotonin-induced L-glutamate release in the prefrontal cortex. LY404039 could modulate glutamatergic activity in limbic and forebrain areas relevant to psychiatric disorders and may be devoid of negative side effects associated with current antipsychotics and anxiolytics. [1]
In Vivo LY404039 demonstrates higher plasma exposure and better oral bioavailability. LY404039 may be valuable in the treatment of neuropsychiatric disorders, including anxiety and psychosis. [1] In wild-type animals, LY404039 significantly reverses d-amphetamine(AMP)-induced increase in ambulations, distance traveled, and reduced time spent at rest. LY404039 reverses phencyclidine (PCP)-evoked behaviors at 10 mg/kg. The antipsychotic-like effects of LY404039 on PCP and AMP-evoked behavioral activation are absent in mGlu2 and mGlu2/3 but not in mGlu3 receptor-deficient mice. In contrast, clozapine and risperidone inhibit PCP-evoked behaviors in both wild-type and mGlu2/3 receptor-deficient mice. [2] LY404039 reduces responding on the EtOH in the pavlovian spontaneous recovery (PSR) test and reduces the expression of an alcohol deprivation effect (ADE) during relapse, but does not affect EtOH responding under maintenance conditions. LY404039 inhibits the expression of alcohol seeking and relapse behavior without altering alcohol self-administration behavior. [3] Moreover, LY404039 attenuates amphetamine- and phencyclidine-induced hyperlocomotion. LY404039 could inhibit conditioned avoidance responding and also reduces fear-potentiated startle in rats and marble burying in mice. Importantly, LY404039 does not produce sedative effects or motor impairment in the conditioned avoidance task. LY404039 also increases dopamine and serotonin release/turnover in the prefrontal cortex. [4]
Clinical Trials LY2140023, an oral prodrug of LY404039, is currently in Phase III clinical trial in patients with schizophrenia.
Features LY2140023 is being investigated as an exciting new medicine that may herald the arrival of third-generation antipsychotic drugs.
Protocol
Kinase Assay [1]
Receptor Binding Assays LY404039 is dissolved in DMSO to make a 10 mM stock solution. Cell lines expressing human mGlu2, mGlu3, mGlu1a, mGlu5a, mGlu4a, mGlu6, mGlu7a, and mGlu8 receptors are derived and cultured in DMEM with 5% dialyzed fetal bovine serum, 1 mM glutamine, 1 mM sodium pyruvate, 50 mg/mL Geneticin, and 0.2 mg/mL hygromycin B. Confluent cultures are passaged weekly. These cells are referred to as rat glutamate transporter (RGT) cells. RGT cells are actually AV12-664 cells, which have been stably transfected with a glutamate transporter (GLAST) to prevent the accumulation of L-glutamate in the cell media. Membranes from mGlu receptor-expressing RGT cells are prepared by harvesting adherent cells from confluent T-150 flasks with a cell scraper. Cells and media are then placed in 50-mL conical tubes and centrifuged at 103 g for 5 min at 4 °C. The supernatant is removed, and the pellet is frozen at –10 °C until use. Frozen pellets are routinely thawed at room temperature for about 10 min when required. Washed cell membranes are prepared by adding 20 mL of 10 mM potassium phosphate buffer, pH 7.6 and 100 mM potassium bromide, at 5 °C and homogenizing with a tissuemizer for 15 s at 90% output. The homogenate is centrifuged at 4.8 × 103 g at 5 °C for 10 min. This last step is repeated twice, the final pellet is resuspended in 10 mL of the same buffer and reserved on ice until initiating the binding assay. [3H]LY341495 Binding: Group II mGlu Receptors: [3H]LY341495 binding is assayed in a reaction mixture containing 10 mM potassium phosphate, pH 7.6, 100 mM potassium bromide, and 1nM [3H]LY341495 (final volume, 500 mL). The incubation is initiated by the addition of the membrane suspension (15 mg of membrane protein) and kept on ice for 30 min. Incubation is terminated by rapid filtration with a cell harvester through glass fiber Whatman GF/B filters prewet with the same potassium phosphate buffer assay buffer at 4 °C. The filters are washed 5 times with 1 mL of buffer. Filter sections are transferred to minivials, and 5 mL liquid scintillation cocktail is added to each vial. Vials are allowed to set for several hours before counting on a liquid scintillation counter. Protein concentrations are quantified by microassay. Nonspecific binding is determined in the presence of 1 mM L-glutamate. [3H]LY341495 Binding: Group III mGlu Receptors: Membranes from cells expressing recombinant human group III mGlu receptors are prepared the same as described for group II mGlu receptor membranes. To start the reaction, washed tissue (0.05–0.20 mg of protein) is added to 10 nM [3H]LY341495 and LY404039 in assay buffer. The final assay volume is 0.5 mL. Nonspecific binding is defined with 1 mM L-glutamate or 1 mM L-serine-O-phosphate (for mGlu7a). Assay plates are incubated for 45 min on ice, and the reaction is terminated by rapid filtration (GF/B filters) and washed twice with 1 mL of ice-cold assay buffer. Filters are placed in minivials, scintillation cocktail is added and counting is done in a liquid scintillation counter. Protein concentration is determined using the microassay. [3H]LY341495 Binding to Rat Brain Membranes: Brain tissue is obtained by decapitating adult male Sprague-Dawley rats (150–250g). The forebrain (cortex, striatum, and hippocampus) is used; the brain tissue is homogenized in 30 mM Tris-HCl buffer, pH 7.6 and 2.5 mM CaCl2, at 5 °C and washed 3 times by centrifugation. The material is incubated at 37 °C for 30 min followed by 3 more washes, finally resuspended in 10 volumes of buffer and frozen at –20 °C. Frozen pellets of rat brain homogenate are thawed on the day of assay and washed 3 times with ice-cold assay buffer (10 mM potassium phosphate containing 100 mM potassium bromide, pH 7.6). The tissue (0.02–0.06 mg of protein) is added to deep-well polypropylene microtiter plates, which contain 1 nM [3H]LY341495 and LY404039 in assay buffer. The final assay volume is 0.5 mL. Nonspecific binding is defined with 1 mM L-glutamate. Assay plates are incubated for 30 minutes on ice, and bound and free radioligands are separated by rapid filtration with 5 × 1 mL of ice-cold assay buffer using Whatman GF/B filters. Protein concentration is determined using the microassay.
Animal Study [2]
Animal Models Separate mGlu2 and mGlu3 receptor knockout mice are established.
Formulation Dissolved in 0.9% saline and the pH is adjusted to 6.0 with 1 M NaOH
Doses 10 mg/kg
Administration Administered via i.p.
References
[1] Rorick-Kehn LM et al. J Pharmacol Exp Ther, 2007, 321(1), 308-317.
[2] Fell MJ et al. J Pharmacol Exp Ther, 2008, 326(1), 209-217.
[3] Rodd ZA et al. Behav Brain Res, 2006, 171(2), 207-215.
[4] Rorick-Kehn LM et al. Psychopharmacology (Berl), 2007, 193(1), 121-136.

参考文献

参考文献

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