LY 379268
目录号 : GC14861LY 379268是一种高选择性、可透过血脑屏障的II组mGlu受体激动剂，对hmGlu2和hmGlu3的EC50值分别为2.69和4.48nM。
Cas No.:191471-52-0
Sample solution is provided at 25 µL, 10mM.
LY 379268 is a highly selective and blood-brain barrier-permeable type II mGlu receptor agonist with EC50 values of 2.69 and 4.48nM for hmGlu2 and hmGlu3, respectively [1]. mGluRs are glutamate receptors and are considered as therapeutic targets for neurodegenerative diseases [2]. LY 379268 has antioxidant and neuroprotective effects [3].
In vitro, LY 379268 (0.1, 1, 10, and 100µM; 1h) treatment significantly increased the surface and total expression of GluA1 and GluA2 subunits of cultured PFC neurons, and significantly increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but did not increase total protein [4]. LY 379268 (1, 10, 100 and 1000nM; 72h) increased the proliferation of cerebellar progenitor cells in a U-shaped concentration-response curve, with maximum stimulation at concentrations of 1 and 10nM, and decreased stimulation at 100nM, and no effect at 1µM. LY 379268 and fluoxetine have a strong synergistic effect in enhancing cell proliferation and inhibiting cAMP formation [5].
In vivo, LY 379268 (0.25, 1, and 2mg/kg/day; single administration; i.p.) treatment significantly enhanced the expression of BDNF mRNA in the cerebral cortex and hippocampal structures (including the dentate gyrus and pyramidal layer) of mice (CA1-CA3) [6]. LY 379268 (3mg/kg/day; single administration; i.p.) treatment restored the binding level of GABAA-R in the prefrontal cortex and hippocampus (especially CA1 area and DG area) of schizophrenia model mice to normal levels, and showed stronger therapeutic potential than olanzapine [7].
References:
[1] Monn, J A et al. “Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors.” Journal of medicinal chemistry vol. 42,6 (1999): 1027-40.
[2] Bond, A et al. “LY379268, a potent and selective Group II metabotropic glutamate receptor agonist, is neuroprotective in gerbil global, but not focal, cerebral ischaemia.” Neuroscience letters vol. 273,3 (1999): 191-4.
[3] E F Sharpe, et al. Systemic pre-treatment with a group II mGlu agonist, LY379268, reduces hyperalgesia in vivo. Br J Pharmacol. 2002 Mar;135(5):1255-62.
[4] Wang M J, Li Y C, Snyder M A, et al. Group II metabotropic glutamate receptor agonist LY379268 regulates AMPA receptor trafficking in prefrontal cortical neurons[J]. PloS one, 2013, 8(4): e61787.
[5] Matrisciano, F et al. “Synergism between fluoxetine and the mGlu2/3 receptor agonist, LY379268, in an in vitro model for antidepressant drug-induced neurogenesis.” Neuropharmacology vol. 54,2 (2008): 428-37.
[6] Di Liberto V, Bonomo A, Frinchi M, et al. Group II metabotropic glutamate receptor activation by agonist LY379268 treatment increases the expression of brain derived neurotrophic factor in the mouse brain[J]. Neuroscience, 2010, 165(3): 863-873.
[7] Engel, Martin et al. “mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia.” Psychopharmacology vol. 233,8 (2016): 1349-59.
LY 379268是一种高选择性、可透过血脑屏障的II组mGlu受体激动剂，对hmGlu2和hmGlu3的EC50值分别为2.69和4.48nM [1]。mGluRs是一种谷氨酸受体，被认为是神经退行性疾病治疗干预的靶点 [2]。LY 379268具有抗氧化和神经保护作用 [3]。
在体外，LY 379268（0.1, 1, 10和100µM; 1h）处理显著增加了培养的PFC神经元GluA1和GluA2亚基的表面和总表达，同时显著增加了细胞外信号调节激酶1/2（ERK1/2）的磷酸化，但没有增加总蛋白 [4]。LY 379268（1, 10, 100和1000nM; 72h）以倒U型浓度-反应曲线增加小脑祖细胞的增殖，在浓度为1和10nM时最大限度地刺激细胞增殖，在100nM时刺激减弱，在1μM时无影响。LY 379268和氟西汀在增强细胞增殖和抑制cAMP形成方面具有强烈的协同作用[5]。
在体内，LY 379268（0.25, 1和2mg/kg/day; 单次给药; i.p.）处理显著增强了小鼠大脑皮层和海马结构（包括齿状回和锥体层）中 BDNF mRNA的表达（CA1-CA3）[6]。LY 379268（3mg/kg/day; 单次给药; i.p.）治疗使精神分裂模型小鼠的前额叶皮质和海马体（特别是CA1区和DG区）中GABAA-R的结合水平恢复到了正常水平，并且显示出比奥氮平更强的治疗潜力 [7]。
| Cell experiment [1]: | |
Cell lines | PFC neuron cells |
Preparation Method | Neurons at 17–18 days in vitro (DIV) were treated with LY 379268 at different concentrations (0.1, 1, 10, and 100µM) or with culture medium as vehicle control for 1h. Briefly, PFC neurons were washed with cold 0.1M phosphate-buffered saline (PBS) and fixed with 4% paraformaldehyde/4% sucrose in 0.1M PBS for 10min at room temperature. Neurons were then blocked with 10% BSA in 0.1M PBS for 1h at room temperature and incubated in the following dilutions of primary antibodies overnight at 4°C: monoclonal rabbit anti-GluA1 N-terminal and anti-GluA2 N-terminal (1∶100). After rinsing with 0.1M PBS for several times, cells were incubated in Dylight 488 or 594 secondary for 1h at room temperature under nonpermeable conditions. After washing with 0.1M PBS, coverslips were mounted in 50% glycerol containing a high quality anti-fade medium Mowiol 488 and DABCO. |
Reaction Conditions | 0.1, 1, 10 and 100µM; 1h |
Applications | LY 379268 treatment significantly increased the surface and total expression of GluA1 and GluA2 subunits of the cultured PFC neurons. |
| Animal experiment [2]: | |
Animal models | C57/BL6 mice |
Preparation Method | Groups of at least four mice for each experiment performed were treated i.p. with saline, or with different doses of (−)-2-oxa-4-aminocyclo [3.1.0] hexane-4,6-dicarboxylic acid LY 379268, ranging from 0.1mg/kg b.w. to 3mg/kg b.w., dissolved in saline. A time-course study was also performed using LY 379268 at dose of 0.25mg/kg. The preferential mGluR2/3 antagonist (2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid LY341495, was injected i.p. at dose of 1mg/kg b.w. 30min before of LY 379268. Mice were killed under deep anesthesia and brain was rapidly frozen in cooled isopentane and stored at −70°C until use for subsequent protein blotting analysis. |
Dosage form | 0.1-3mg/kg/day; Single-dose; i.p. |
Applications | LY 379268 treatment significantly enhanced the expression of BDNF mRNA in the cerebral cortex and hippocampal structures (including the dentate gyrus and pyramidal layer) of mice (CA1-CA3). |
References: | |
| Cas No. | 191471-52-0 | SDF | |
| 化学名 | (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid | ||
| Canonical SMILES | OC([C@@H]1[C@@H]2[C@H]1OC[C@]2(C(O)=O)N)=O | ||
| 分子式 | C7H9NO5 | 分子量 | 187.15 |
| 溶解度 | 25 mM in Water | 储存条件 | Store at 4°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 5.3433 mL | 26.7165 mL | 53.4331 mL |
| 5 mM | 1.0687 mL | 5.3433 mL | 10.6866 mL |
| 10 mM | 0.5343 mL | 2.6717 mL | 5.3433 mL |
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