Structural modifications of neuroprotective anti-Parkinsonian (-)-N6-(2-(4-(biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264): an effort toward the improvement of in vivo efficacy of the parent molecule.
Structural modifications of neuroprotective anti-Parkinsonian (-)-N6-(2-(4-(biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264): an effort toward the improvement of in vivo efficacy of the parent molecule.
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DOI：
10.1021/jm401883v
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发表时间：
2014-02-27
影响因子：
7.3
通讯作者：
Dutta A
中科院分区：
文献类型：
--
作者：
Modi G;Antonio T;Reith M;Dutta A
在我们开发用于治疗帕金森病（PD）的多功能多巴胺D2/D3激动剂药物的总体目标中，我们先前合成了有效的D3偏好激动剂D-264（1a），其在两种PD动物模型中表现出神经保护特性。为了增强1a的体内功效，进行了结构-活性关系研究。竞争性结合和[35 S]GTPγS功能测定将化合物（−）-9b鉴定为具有优先D3激动剂活性的先导分子之一（EC 50（GTPγS）; D3 = 0.10 nM; D2/D3（EC 50）：159）。化合物（-）-9b和（-）-8b在两种PD动物模型（利血平化和6-羟基多巴胺（OHDA）诱导的单侧损伤大鼠）中表现出高的体内活性。另一方面，除非将化合物溶解在5-10% β-羟丙基环糊精溶液中，否则1a在这些模型中未显示任何体内活性。铅化合物具有明显的自由基清除活性。多巴胺能MN 9D细胞的体外实验表明，1a和（−）-9b都能保护神经免受MPP+的毒性。
In our overall goal to develop multifunctional dopamine D2/D3 agonist drugs for the treatment of Parkinson’s disease (PD), we previously synthesized potent D3 preferring agonist D-264 (1a), which exhibited neuroprotective properties in two animal models of PD. To enhance the in vivo efficacy of 1a, a structure–activity relationship study was carried out. Competitive binding and [35S]GTPγS functional assays identified compound (−)-9b as one of the lead molecules with preferential D3 agonist activity (EC50(GTPγS); D3 = 0.10 nM; D2/D3 (EC50): 159). Compounds (−)-9b and (−)-8b exhibited high in vivo activity in two PD animal models, reserpinized and 6-hydroxydopamine (OHDA)-induced unilateral lesioned rats. On the other hand, 1a failed to show any in vivo activity in these models unless the compound was dissolved in 5–10% beta-hydroxy propyl cyclodextrin solution. Lead compounds exhibited appreciable radical scavenging activity. In vitro experiments with dopaminergic MN9D cells indicated neuroprotection by both 1a and (−)-9b from toxicity of MPP+.
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影响因子：
7.3
作者：
Doll, MKH;Nichols, DE;Mailman, RB
通讯作者：
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7.3
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影响因子：
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影响因子：
3.5
作者：
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