Development of (S)-N6-(2-(4-(isoquinolin-1-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]-thiazole-2,6-diamine and its analogue as a D3 receptor preferring agonist: potent in vivo activity in Parkinson's disease animal models.
Development of (S)-N6-(2-(4-(isoquinolin-1-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]-thiazole-2,6-diamine and its analogue as a D3 receptor preferring agonist: potent in vivo activity in Parkinson's disease animal models.
复制标题
DOI：
10.1021/jm901184n
复制
发表时间：
2010-02-11
影响因子：
7.3
通讯作者：
Dutta AK
中科院分区：
文献类型：
--
作者：
Ghosh B;Antonio T;Zhen J;Kharkar P;Reith ME;Dutta AK
在这里，我们报道了一系列新型杂化化合物的构效关系研究，其中芳香族疏水部分与哌嗪环连接的结构改变和芳香族四氢萘部分的生物等位取代。用表达D2或D3受体的HEK-293细胞与氚螺环酮进行结合实验，计算抑制常数(Ki)。用表达人D2受体的CHO细胞和表达人D3受体的ATT-20细胞对化合物刺激γ与S结合的功能活性进行了评价。结果表明，化合物(−)-24c(D-301)是对D3受体具有优先激动剂活性的先导分子之一(γS)，D3=0.52nM；D2/D3(EC50)：223。化合物(−)-24b和(−)-24c具有较强的自由基清除活性。两个先导化合物(−)-24b和(−)-24c在两种帕金森病(PD)动物模型、利血平大鼠模型和6-OH-DA单侧损毁大鼠模型上均显示出较高的体内活性。未来的研究将探索这些化合物在帕金森病神经保护治疗中的潜在用途。
Here we report structure-activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were carried out. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (Ki). Functional activity of selected compounds in stimulating GTPγS binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. SAR results identified compound (−)-24c (D-301) as one of the lead molecules with preferential agonist activity for D3 receptor (EC50 (GTPγS); D3 = 0.52 nM; D2/D3 (EC50): 223). Compounds (−)-24b and (−)-24c exhibited potent radical scavenging activity. The two lead compounds (−)-24b and (−)-24c exhibited high in vivo activity in two Parkinson’s disease (PD) animal models, reserpinized rat model and 6-OH-DA induced unilaterally lesioned rat model. Future studies will explore potential use of these compounds in the neuroprotective therapy for PD.
登录
查看更多内容
影响因子：
4.7
作者：
Bellucci, Arianna;Collo, Ginetta;Spano, PierFranco
通讯作者：
Spano, PierFranco
影响因子：
4.7
作者：
Gu, M;Irvani, M;Schapira, AHV
通讯作者：
Schapira, AHV
影响因子：
3.5
作者：
Dutta, AK;Venkataraman, SK;Reith, MEA
通讯作者：
Reith, MEA
影响因子：
7.3
作者：
Biswas, Swati;Hazeldine, Stuart;Dutta, Aloke K.
通讯作者：
Dutta, Aloke K.
影响因子：
3.5
作者：
Chen, Sheng;Zhang, Xiaojie;Le, Weidong
通讯作者：
Le, Weidong