GNE 0723是一种选择性作用于GluN2A亚基且能穿透血脑屏障的N-甲基-D-天冬氨酸受体（NMDAR）正向变构调节剂（PAM），其半数有效浓度（EC50）为0.021μM，最大增强作用为152%。
Cas No.:1883518-31-7
Sample solution is provided at 25 µL, 10mM.
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GNE 0723 is a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs, with an EC50 of 0.021μM and a maximal potentiation of 152%[1,2].
In vitro, Whole-cell recordings at room temperature (RT) from CHO cells expressing GluN2A-containing NMDARs showed that 1μM GNE 0723 enhanced the peak current and slowed the current deactivation in response to brief pulses of glutamate (Glu)[3].
In vivo, mouse clearance of GNE 0723 was 26mL·min–1·kg–1 and oral bioavailability was 24%[1]. GNE 0723 (3mg/kg; oral; every other day for 5 weeks) treatment improved memory retention in J20 mice and improved long-term memory consolidation in J20 and WT mice by the Morris water maze (MWM) test[3]. GNE 0723 (3mg/kg; oral; every other day for 5 weeks) enhances fear learning in Scn1a-KI mice[3].
References:
[1]. Villemure, Elisia, et al. "GluN2A-selective pyridopyrimidinone series of NMDAR positive allosteric modulators with an improved in vivo profile." ACS Medicinal Chemistry Letters 8.1 (2017): 84-89.
[2]. Li, Zhongtang, et al. "Discovery of novel and potent N-methyl-d-aspartate receptor positive allosteric modulators with antidepressant-like activity in rodent models." Journal of Medicinal Chemistry 64.9 (2021): 5551-5576.
[3]. Hanson, Jesse E., et al. "GluN2A NMDA receptor enhancement improves brain oscillations, synchrony, and cognitive functions in Dravet syndrome and Alzheimer’s disease models." Cell reports 30.2 (2020): 381-396.
GNE 0723是一种选择性作用于GluN2A亚基且能穿透血脑屏障的N-甲基-D-天冬氨酸受体（NMDAR）正向变构调节剂（PAM），其半数有效浓度（EC50）为0.021μM，最大增强作用为152%[1,2]。
在体外，室温下对表达含GluN2A的NMDAR的CHO细胞进行全细胞记录显示，1μM的 GNE 0723 能增强谷氨酸（Glu）短暂脉冲刺激下的峰值电流，并减缓电流失活速度[3]。
在体内，小鼠对GNE 0723的清除率为26mL·min–1·kg–1，口服生物利用度为24%[1]。通过莫里斯水迷宫（MWM）测试，GNE 0723（3mg/kg；口服；每隔一天给药一次，持续5周）治疗可改善J20小鼠的记忆保持能力，并提高J20和野生型小鼠的长期记忆能力[3]。GNE 0723（3mg/kg；口服；每隔一天给药一次，持续5周）能增强Scn1a-KI小鼠的恐惧学习能力[3]。
| Cell experiment [1]: | |
Cell lines | CHO cell lines |
Preparation Method | Whole-cell patch-clamp recordings were made from CHO cell lines, 1μM GNE 0723 and 0.03-100μM Glu was applied for a 5ms pulse duration using a 2-barrel theta tube perfusion system with a P-601.30L PiezoMove linear actuator. |
Reaction Conditions | 1μM |
Applications | GNE 0723 at 1μM enhanced NMDAR currents evoked by a wide range of Glu concentrations. |
| Animal experiment [1]: | |
Animal models | Sex-mixed 4−6-month-old J20 |
Preparation Method | Doses of GNE 0723 were administered via oral gavage as 0.5% methylcellulose and 0.2% Tween 80 (MCT) suspension. Vehicle was used as control. Drug doses for GNE 0723 are expressed as mg/kg of free base. |
Dosage form | 3mg/kg; oral; every other day for 5 weeks. |
Applications | An early probe trial 24 h after 3 days of MWM training revealed a significant quadrant preference (reference memory) in GNE 0723-treated J20 mice. |
References: | |
| Cas No. | 1883518-31-7 | SDF | |
| Canonical SMILES | N#C[C@H]1[C@H](C2=C(C(F)(F)F)SC3=NC(CN4N=C(C(F)(F)F)C=C4Cl)=CC(N32)=O)C1 | ||
| 分子式 | C16H8ClF6N5OS | 分子量 | 467.78 |
| 溶解度 | DMSO : 190 mg/mL (406.17 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1378 mL | 10.6888 mL | 21.3776 mL |
| 5 mM | 427.6 μL | 2.1378 mL | 4.2755 mL |
| 10 mM | 213.8 μL | 1.0689 mL | 2.1378 mL |
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动物数量 | 只 |
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- Purity: >97.00% Appearance: A solid
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