Structure-Activity Relationship and Neuroprotective Activity of 1,5-Dihydro-2H-naphtho[1,2-b][1,4]diazepine-2,4(3H)-diones as P2X4 Receptor Antagonists.
Structure-Activity Relationship and Neuroprotective Activity of 1,5-Dihydro-2H-naphtho[1,2-b][1,4]diazepine-2,4(3H)-diones as P2X4 Receptor Antagonists.
复制标题
DOI：
10.1021/acs.jmedchem.2c01197
复制
发表时间：
2022-10-27
影响因子：
7.3
通讯作者：
Jacobson KA
中科院分区：
文献类型：
--
作者：
Toti KS;Verma R;McGonnigle MJ;Gamiotea Turro D;Wen Z;Lewicki SA;Liang BT;Jacobson KA
我们分析了已知拮抗剂1,5-二氢- 2h -萘[1,2-b][1,4]二氮平-2,4(3H)-二酮的P2X4受体结构-活性关系。经过对合成路线的广泛修改，4-吡啶基21u （MRS4719）和6-甲基22c （MRS4596）类似物对人（h) P2X4R最有效（IC50分别为0.503和1.38 μM），对hP2X1R， hP2X2/3R， hP2X3R有选择性）。因此，萘6-而非7-位可被取代，n -苯基环偶氮扫描鉴定出21u的活性比5高3倍。化合物21u和22c对缺血性脑卒中小鼠模型具有神经保护和学习记忆增强作用，其效价为21u和22c。21u分别在脑卒中后3天和35天剂量依赖性地减少梗死体积和脑萎缩。与临床意义相关的是，21u还减少了原代人单核细胞源性巨噬细胞中atp诱导的[Ca2+]i内流。这项研究表明P2X4R拮抗剂治疗缺血性卒中的转化潜力，包括老年人群。
We analyzed the P2X4 receptor structure–activity relationship of a known antagonist 5, a 1,5-dihydro-2H-naphtho[1,2-b][1,4]diazepine-2,4(3H)-dione. Following extensive modification of the reported synthetic route, 4-pyridyl 21u (MRS4719) and 6-methyl 22c (MRS4596) analogues were most potent at human (h) P2X4R (IC50 0.503 and 1.38 μM, respectively, and selective versus hP2X1R, hP2X2/3R, hP2X3R). Thus, the naphthalene 6-, but not 7-position was amenable to substitution, and an N-phenyl ring aza-scan identified 21u with 3-fold higher activity than 5. Compounds 21u and 22c showed neuroprotective and learning- and memory-enhancing activities in a mouse middle cerebral artery occlusion (MCAO) model of ischemic stroke, with potency of 21u > 22c. 21u dose-dependently reduced infarct volume and reduced brain atrophy at 3 and 35 days post-stroke, respectively. Relevant to clinical implication, 21u also reduced ATP-induced [Ca2+]i influx in primary human monocyte-derived macrophages. This study indicates the translational potential of P2X4R antagonists for treating ischemic stroke, including in aging populations.
登录
查看更多内容
乙醇差异调节BV2小胶质细胞中的P2X4和P2X7受体活性和功能。
影响因子：
4.7
作者：
Asatryan L;Ostrovskaya O;Lieu D;Davies DL
通讯作者：
Davies DL
DOI：
10.1016/j.ynpai.2017.04.001
发表时间：
2017-01-01
期刊：
Neurobiology of pain (Cambridge, Mass.)
影响因子：
--
作者：
Malcangio, Marzia
通讯作者：
Malcangio, Marzia
影响因子：
11
作者：
Bertin, Eleonore;Deluc, Thomas;Boue-Grabot, Eric
通讯作者：
Boue-Grabot, Eric
影响因子：
4
作者：
Antonioli, Luca;Blandizzi, Corrado;Hasko, Gyorgy
通讯作者：
Hasko, Gyorgy
影响因子：
2
作者：
Dunton CL;Purves JT;Hughes FM Jr;Jin H;Nagatomi J
通讯作者：
Nagatomi J