PDF(Pubmed)
Abstract：
The future of therapy for neurodegenerative diseases (NDs) relies on new strategies targeting multiple pharmacological pathways. Our research led to obtaining the compound AR71 [(E)-3-(3,4,5-trimethoxyphenyl)-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)prop-2-en-1-one], which has high affinity for human H3R (Ki = 24 nM) and selectivity towards histamine H1 and H4 receptors (Ki > 2500 nM), and showed anti-inflammatory activity in a model of lipopolysaccharide-induced inflammation in BV-2 cells. The presented tests confirmed its antagonist/inverse agonist activity profile and good metabolic stability while docking studies showed the binding mode to histamine H1, H3, and H4 receptors. In in vitro tests, cytotoxicity was evaluated at three cell lines (neuroblastoma, astrocytes, and human peripheral blood mononuclear cells), and a neuroprotective effect was observed in rotenone-induced toxicity. In vivo experiments in a mouse neuropathic pain model demonstrated the highest analgesic effects of AR71 at the dose of 20 mg/kg body weight. Additionally, AR71 showed antiproliferative activity in higher concentrations. These findings suggest the need for further evaluation of AR71\'s therapeutic potential in treating ND and CNS cancer using animal experimental models.
摘要：
神经退行性疾病（ND）治疗的未来依赖于靶向多种药理途径的新策略。我们的研究导致获得化合物AR71[(E)-3-(3,4,5-三甲氧基苯基)-1-(4-(3-(哌啶-1-基)丙氧基)苯基)丙-2-烯-1-酮]，对人H3R具有高亲和力（Ki=24nM），对组胺H1和H4受体具有选择性（Ki>2500nM），并在脂多糖诱导的BV-2细胞炎症模型中显示抗炎活性。提出的测试证实了其拮抗剂/反向激动剂活性谱和良好的代谢稳定性，而对接研究显示了与组胺H1，H3和H4受体的结合模式。在体外试验中,在三种细胞系（神经母细胞瘤，星形胶质细胞,和人外周血单核细胞），在鱼藤酮诱导的毒性中观察到神经保护作用。在小鼠神经性疼痛模型中的体内实验证明了AR71在20mg/kg体重的剂量下的最高镇痛效果。此外,AR71在较高浓度下显示抗增殖活性。这些研究结果表明，需要使用动物实验模型进一步评估AR71在治疗ND和CNS癌症方面的治疗潜力。
