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]。