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Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer's Disease.
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-03-19 , DOI: 10.1021/acs.jmedchem.9b02080
Sònia Abás 1 , Sergio Rodríguez-Arévalo 1 , Andrea Bagán 1 , Christian Griñán-Ferré 2 , Foteini Vasilopoulou 2 , Iria Brocos-Mosquera 3 , Carolina Muguruza 3 , Belén Pérez 4 , Elies Molins 5 , F Javier Luque 6 , Pilar Pérez-Lozano 7 , Steven de Jonghe 8 , Dirk Daelemans 8 , Lieve Naesens 8 , José Brea 9 , M Isabel Loza 9 , Elena Hernández-Hernández 10 , Jesús A García-Sevilla 10 , M Julia García-Fuster 10 , Milica Radan 11 , Teodora Djikic 11 , Katarina Nikolic 11 , Mercè Pallàs 2 , Luis F Callado 3 , Carmen Escolano 1
Affiliation  

Imidazoline I2 receptors (I2-IR), widely distributed in the CNS and altered in patients that suffer from neurodegenerative disorders, are orphans from a structural point of view, and new I2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and three-dimensional quantitative structure–activity relationship (3D-QSAR) studies of a new family of bicyclic α-iminophosphonates endowed with relevant affinities for human brain I2-IR. Acute treatment in mice with a selected compound significantly decreased Fas-associated protein with death domain (FADD) in the hippocampus, a key signaling mediator of neuroprotective actions. Additionally, in vivo studies in the familial Alzheimer’s disease 5xFAD murine model revealed beneficial effects in behavior and cognition. These results are supported by changes in molecular pathways related to cognitive decline and Alzheimer’s disease. Therefore, bicyclic α-iminophosphonates are tools that may open new therapeutic avenues for I2-IR, particularly for unmet neurodegenerative conditions.

中文翻译:

双环α-亚氨基膦酸酯作为阿尔茨海默氏病的高亲和力咪唑啉I2受体配体。

从结构的观点来看,咪唑啉I 2受体(I 2 -IR)广泛分布在中枢神经系统中,并在患有神经退行性疾病的患者中发生改变,从结构的角度来看是孤儿,迫切需要新的I 2 -IR配体来改善其药理特性。我们报告的合成和三维定量结构-活性关系(3D-QSAR)研究的双环的α-亚氨基膦酸酯的新家族,具有与人脑I 2 -IR相关的亲和力。用选定化合物对小鼠进行的急性治疗可显着降低海马Fas相关蛋白的死亡域(FADD),这是神经保护作用的关键信号传递介质。此外,体内对家族性阿尔茨海默氏病5xFAD小鼠模型的研究表明,它在行为和认知方面具有有益作用。这些结果得到与认知下降和阿尔茨海默氏病相关的分子途径变化的支持。因此,双环α-亚氨基膦酸酯是可以为I 2 -IR,特别是对于未满足的神经退行性疾病开辟新的治疗途径的工具。
更新日期:2020-03-20
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