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受注：045-509-1970 |
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化学情報
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Synonyms | N/A | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
| 化学式 | C7H9NO6S |
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| 分子量 | 235.22 | CAS No. | 635318-11-5 | |
| Solubility (25°C)* | 体外 | DMSO | 1 mg/mL (4.25 mM) | |
| Water | Insoluble | |||
| Ethanol | Insoluble | |||
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* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. |
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溶剤液（一定の濃度）を調合する
生物活性
| 製品説明 | LY404039 is a potent agonist of recombinant human mGlu2/mGlu3 receptors with Ki of 149 nM/92 nM, shows >100-fold selectivity over ionotropic glutamate receptors, glutamate transporters, and other receptors. Phase 3. |
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| 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] |
| 特徴 | Under investigation as an exciting new medicine that may herald the arrival of third-generation antipsychotic drugs. |
プロトコル(参考用のみ)
| キナーゼアッセイ | Receptor Binding Assays | |
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| 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. | ||
| 動物実験 | 動物モデル | Separate mGlu2 and mGlu3 receptor knockout mice are established. |
| 投薬量 | 10 mg/kg | |
| 投与方法 | Administered via i.p. | |
参考
カスタマーフィードバック
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Data from [PLoS One, 2011, 6, e22235]
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, , Dr. Philip Seeman, Department of Pharmacology, University of Toronto
Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：
| Peripubertal mGluR2/3 Agonist Treatment Prevents Hippocampal Dysfunction and Dopamine System Hyperactivity in Adulthood in MAM Model of Schizophrenia [ Schizophr Bull, 2021, sbab047] | PubMed: 33928393 |
| The mGluR2/3 agonist pomaglumetad methionil normalizes aberrant dopamine neuron activity via action in the ventral hippocampus [ Neuropsychopharmacology, 2020, 10.1038/s41386-020-0764-2] | PubMed: 32663839 |
| Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo. [ Sci Rep, 2019, 9(1):14247] | PubMed: 31582824 |
| Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. [ Sci Signal, 2016, 9(410):ra5] | PubMed: 26758213 |
| Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia [ Sci Signal, 2016, 9(410):ra5] | PubMed: 26758213 |
| Glutamate Drug Reduces Dopamine Inhibition of Phosphorylation [Su P, et al. Synapse, 2015, 70:45–48] | PubMed: 26583745 |
| Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades. [Delille HK, et al. Neuropharm, 2012, 62(7):2184-91] | PubMed: 22300836 |
| Reduced cAMP, Akt activation and p65-c-Rel dimerization: mechanisms involved in the protective effects of mGluR3 agonists in cultured astrocytes. [Durand D, et al. PLoS One, 2011, 6(7):e22235] | PubMed: 21779400 |
| Glutamate agonist LY404,039 for treating schizophrenia has affinity for the dopamine D2High receptor. [Seeman P, et al. Synapse, 2009, 63(10):935-9] | PubMed: 19588471 |
長期の保管のために-20°Cの下で製品を保ってください。
人間や獣医の診断であるか治療的な使用のためにでない。
各々の製品のための特定の保管と取扱い情報は、製品データシートの上で示されます。大部分のSelleck製品は、推薦された状況の下で安定です。製品は、推薦された保管温度と異なる温度で、時々出荷されます。長期の保管のために必要とされてそれと異なる温度で、多くの製品は、短期もので安定です。品質を維持するが、夜通しの積荷のために最も経済的な貯蔵状況を用いてあなたの送料を保存する状況の下に、製品が出荷されることを、我々は確実とします。製品の受領と同時に、製品データシートの上で貯蔵推薦に従ってください。