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神经药理及新药发现课题组周中振副教授/徐江平教授以共同通讯作者
在药物化学1区期刊ACS Chem Neurosci上发表研究论文
近日,神经药理及新药发现课题组周中振副教授/徐江平教授以共同通讯作者在药物化学1区期刊ACS Chem Neurosci上发表了题为“Discovery of N-Alkyl Catecholamides as Selective Phosphodiesterase-4 Inhibitors with Anti-neuroinflammation Potential Exhibiting Antidepressant-like Effects at Non-emetic Doses”的研究论文。
前期徐江平教授实验室通过脑内注射携带PDE4 shRNA的慢病毒敲低小鼠海马组织内磷酸二酯酶4 (PDE4)的表达,并在此基础上证实了PDE4对神经炎症的调控及抗抑郁样作用。但临床上没有很好的PDE4抑制剂,现有的PDE4抑制剂普遍存在严重致呕吐的不良反应,致使临床应用受阻。针对这一问题,周中振副教授/徐江平教授研究团队近几年致力于设计合成新型高选择性PDE4抑制剂及变构调节剂来减少致呕吐反应,同时保留其原有的药效学作用。
近来,神经药理及新药发现课题组对实验室前期合成的先导化合物FCPE07的进一步改造修饰,得到系列N-烷基邻苯二酰胺类化合物。通过PDE4酶抑制活性筛选得到10个目标化合物,这些化合物抑制PDE4的IC50达到纳摩尔级。其中两个化合物对PDE4的选择性分别高于其他PDE亚型5000倍及2100倍以上。与PDE4D的分子对接显示这两个化合物的得分分别为9.3383和 9.1722(经典PDE4抑制剂咯利普兰得分为9.018)。在小胶质细胞中,通过LPS诱导神经炎症,发现得到的化合物可显著抑制TNF-alpha及iNOS、COX-2的表达,药代动力学研究显示这些化合物可以透过血脑屏障,进入中枢神经系统。动物实验显示这些化合物能产生显著的抗抑郁效应,但不影响动物的自主活动。尤其重要的是在小鼠翻正反射及比格犬致呕吐实验中均未见呕吐样反应,显示出极大的开发价值及临床应用价值。
该论文受到国家自然科学基金-广东联合基金、国家自然科学基金、新药创制重大专项、广东省科技计划、广东省高等学校优秀青年教师培育计划等基金资助。ACS Chem Neurosci为美国化学会(ACS)主办的期刊,小类药物化学1区杂志,属于Top级杂志,IF=4.348。
1. Zhou ZZ, Cheng YF, Zou ZQ, Ge BC, Yu H, Huang C, Wang HT, Yang XM, Xu JP. Discovery of N-Alkyl Catecholamides as Selective Phosphodiesterase-4 Inhibitors with Anti-neuroinflammation Potential Exhibiting Antidepressant-like Effects at Non-emetic Doses. ACS Chem Neurosci. 2016 Oct 3. [Epub ahead of print]
Abstract
Depression involving neuroinflammation is one of the most common disabling and life-threatening psychiatric disorders. Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by their major side effect of emesis. To obtain more selective PDE4 inhibitors with antidepressant and anti-neuroinflammation potential and less side effect of emesis, we designed and synthesized a series of N-alkyl catecholamides by modifying the 4-methoxybenzyl group of our hit compound, FCPE07, with an alkyl side chain. Among these compounds, ten compounds displayed sub-micromolar IC50 values in the mid- to low-nanomolar range. Moreover, 4-difluoromethoxybenzamides 10g and 10j, bearing isopropyl groups, exhibited the highest PDE4 inhibitory activities, with IC50 values in the low-nanomolar range and with higher selectivities for PDE4 (approximately 5000-fold and 2100-fold over other PDEs, respectively). Furthermore, compound 10j displayed anti-neuroinflammation potential, promising antidepressant-like effects, and a zero incidence rate of emesis at 0.8 mg/kg within 180 min.