PNU 282987
目录号 : GC12952
PNU 282987是一种选择性α7烟碱乙酰胆碱受体（α7nAChR）激动剂，与抗炎途径相关，也是5-HT3受体的拮抗剂，PNU 282987对α7nAChR的EC50为154nM （Ki α7nAChR=27nM，大鼠脑匀浆），对5-HT3受体的IC50为4541nM （Ki 5-HT3R=1662nM, GR-65630）。
Cas No.:123464-89-1
Sample solution is provided at 25 µL, 10mM.
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PNU 282987 is a selective α7 nicotinic acetylcholine receptor (α7nAChR) agonist associated with an anti-inflammatory pathway as well as an antagonist of the 5-HT3 receptor, the EC50 of PNU 282987 for α7nAChR is 154nM (Ki α7nAChR=27nM, rat brain homogenates) while IC50 for 5-HT3 receptor is 4541nM (Ki 5-HT3R=1662nM, GR-65630) [1][2]. α7nAChR agonists can restore the anti-inflammatory function in the brain by activating α7nAChR and competing against α7 nAChR inhibitors such as amyloid beta at the orthosteric binding site of α7nAChR[3]. 5-HT3 receptor (5-HT3R) antagonist blocks afferent and efferent synaptic transmission by blocking fast depolarizing response mediated by Na+, K+, and Ca2+, however, the binding site of PNU 282987 at 5-HT3 receptor is not well-identified[4].
in vitro experiments show that PNU 282987(5μM, 30min treatment) reduce TNF-α release in full-length human α7nAChR-expressing mouse fibroblast NIH3T3 treated with lipopolysaccharid[5]. PNU 282987(3μM, 7min treatment) triggers a robust concentration-dependent increase in ERK1/2 phosphorylation in PC12 cells pretreated with p38 inhibitors[6]. PNU 282987(5 and 50μM, 48h treated) also attenuated BCAA-induced injury in primary murine cardiomyocytes[7].
In vivo experiments show that PNU 282987(3mg/kg, once, i.p) has protective effects on intestinal epithelial barrier dysfunction in LPS-induced endotoxemic rats[8]. PNU 282987 (2mg/ml, once, 40min recovery, i.p) is able to reverse scopolamine-induced memory impairment and restore it back to normal levels[9].
References:
[1]. Pohanka, Miroslav. “Alpha7 nicotinic acetylcholine receptor is a target in pharmacology and toxicology.” *International journal of molecular sciences* vol. 13,2 (2012): 2219-2238. doi:10.3390/ijms13022219.
[2]. Bodnar, Alice L et al. “Discovery and structure-activity relationship of quinuclidine benzamides as agonists of alpha7 nicotinic acetylcholine receptors.” *Journal of medicinal chemistry* vol. 48,4 (2005): 905-8. doi:10.1021/jm049363q
[3]. Cecon, Erika et al. “Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor.” *British journal of pharmacology* vol. 176,18 (2019): 3475-3488. doi:10.1111/bph.14688
[4]. Machu, Tina K. “Therapeutics of 5-HT3 receptor antagonists: current uses and future directions.” *Pharmacology & therapeutics* vol. 130,3 (2011): 338-47. doi:10.1016/j.pharmthera.2011.02.003.
[5]. Li, Dong-Jie et al. “Overexpressed alpha7 nicotinic acetylcholine receptor inhibited proinflammatory cytokine release in NIH3T3 cells.” *Journal of bioscience and bioengineering* vol. 108,2 (2009): 85-91. doi:10.1016/j.jbiosc.2009.03.004.
[6]. Gubbins, Earl J et al. “Alpha7 nAChR-mediated activation of MAP kinase pathways in PC12 cells.” *Brain research* vol. 1328 (2010): 1-11. doi:10.1016/j.brainres.2010.02.083.
[7]. Jiang, Yu-Jie et al. “Excessive ROS production and enhanced autophagy contribute to myocardial injury induced by branched-chain amino acids: Roles for the AMPK-ULK1 signaling pathway and α7nAChR.” *Biochimica et biophysica acta. Molecular basis of disease* vol. 1867,1 (2021): 165980. doi:10.1016/j.bbadis.2020.165980.
[8]. Zhang, Ying et al. “PNU-282987 Attenuates Intestinal Epithelial Barrier Dysfunction in LPS-Induced Endotoxemia.” *Inflammation* vol. 43,2 (2020): 417-424. doi:10.1007/s10753-019-01096-w.
[9]. Pandya, Anshul A, and Jerrel L Yakel. “Activation of the α7 nicotinic ACh receptor induces anxiogenic effects in rats which is blocked by a 5-HT₁a receptor antagonist.” *Neuropharmacology* vol. 70 (2013): 35-42. doi:10.1016/j.neuropharm.2013.01.004.
PNU 282987是一种选择性α7烟碱乙酰胆碱受体（α7nAChR）激动剂，与抗炎途径相关，也是5-HT3受体的拮抗剂，PNU 282987对α7nAChR的EC50为154nM （Ki α7nAChR=27nM，大鼠脑匀浆），对5-HT3受体的IC50为4541nM （Ki 5-HT3R=1662nM, GR-65630）[1][2]。α7nAChR激动剂通过激活α7nAChR，在α7nAChR的正构结合位点与α7nAChR抑制剂（如β淀粉样蛋白）竞争，恢复脑内的抗炎功能[3]。5-HT3受体（5-HT3R）拮抗剂通过阻断Na+、K+和Ca2+介导的快速去极化反应来阻断传入和输出突触传递，但PNU 282987在5-HT3受体上的结合位点尚未明确[4]。
体外实验表明，PNU 282987 （5μM，处理30min）可减少脂多糖处理的全长人α7nachr表达小鼠成纤维细胞NIH3T3中TNF-α的释放[5]。PNU 282987 （3μM，处理7min）在p38抑制剂预处理的PC12细胞中触发ERK1/2磷酸化的浓度依赖性增强[6]。PNU 282987 （5μM和50μM， 处理48h）也能减轻bcaa诱导的原代小鼠心肌细胞损伤[7]。
体内实验表明，PNU 282987 （3mg/kg，单次，腹腔注射）对lps诱导的大鼠肠上皮屏障功能障碍有保护作用[8]。PNU 282987 （2mg/ml，单次，恢复40min，腹腔注射）能够逆转东莨菪碱引起的记忆损伤，使其恢复到正常水平[9]。
| Cell experiment [1]: | |
Cell lines | RAW264.7, MOVAS |
Preparation Method | The cells were plated on 60-mm culture dishes at a density of 2×105 cells/ml, permitted to adhere in complete medium for 24h, and changed to serum-free medium (RAW264.7 cells) or 1 % serum medium (MOVAS cells) to serum starve the cells overnight. The next day, the medium was changed and the cells were pretreated with PNU 282987 for 30min prior to being supplemented with an appropriate concentration of nicotine. After the cells were exposed to nicotine for 3h, both the supernatant and cells were harvested. |
Reaction Conditions | 0.1, 1, 10, and 100µM for 30min |
Applications | Cells were pretreated with PNU 282987 (α7nAChR agonist) prior to nicotine exposure, the nicotine-induced upregulation of VCAM-1, MMP-2, MMP-9, and p-JNK was suppressed, with a joint treatment producing a more significant inhibitory effect. Moreover, PNU 282987 had a comparable inhibitory effect on VCAM-1, MMP-2, and MMP-9 expressions and JNK activation via phosphorylation. |
| Animal experiment [2]: | |
Animal models | Male C57BL/6 mice |
Preparation Method | Based on salt weight and concentration, compounds were dissolved in 0.9% saline, the injection volume is 1ml/kg body weight, followed by daily doses at 24h intervals. Control animals were injected with saline. |
Dosage form | 1mg/kg/day, 21 days maximum, i.p |
Applications | PNU 282987 reduced inflammatory factors (MCP-1, IL-1β, MMP-9, TNF-α, HMGB1, TLR2), promoted the polarization of macrophage/microglia into anti-inflammatory subtypes(CD206), repaired blood-brain barrier injury (ZO-1, Claudin-5, Occludin), alleviated acute brain edema and then recovered neurological dysfunction. |
References: | |
| Cas No. | 123464-89-1 | SDF | |
| 化学名 | 4-chloro-N-((1S,3R,4S)-quinuclidin-3-yl)benzamide | ||
| Canonical SMILES | ClC1=CC=C(C=C1)C(N[C@@H]2[C@H](CC3)CC[N@]3C2)=O | ||
| 分子式 | C14H17ClN2O | 分子量 | 264.75 |
| 溶解度 | DMF: 10 mg/ml,DMSO: 30 mg/ml,Ethanol: 20 mg/ml,PBS (pH 7.2): 5 mg/ml | 储存条件 | 4°C, sealed storage, away from moisture. |
| 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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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.7771 mL | 18.8857 mL | 37.7715 mL |
| 5 mM | 0.7554 mL | 3.7771 mL | 7.5543 mL |
| 10 mM | 0.3777 mL | 1.8886 mL | 3.7771 mL |
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| 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 | ||||||||||
| 计算重置 | ||||||||||
计算结果:
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，
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2.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
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