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Retinoid X Receptor Alpha Nitro-ligand Z-10 and Its Optimized Derivative Z-36 Reduce β-Amyloid Plaques in Alzheimer’s Disease Mouse Model
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2018-07-11 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00096
Gaoang Ren 1 , Wei Bao 1 , Zhiping Zeng 1 , Weidong Zhang 1 , Ce Shang 1 , Maosi Wang 1 , Ying Su 1, 2 , Xiao-kun Zhang 1, 2 , Hu Zhou 1
Affiliation  

Bexarotene, an agonist of retinoid X receptor alpha (RXRα), has been shown to increase the expression of apoE, ABCA1, and ABCG1 by activating RXR/LXR and RXR/PPAR heterodimers, resulting in amyloid β (Aβ)-protein clearance in the brain of an Alzheimer’s disease (AD) mouse model and reversal of mouse cognitive deficits. Nitrostyrene derivative Z-10 is the first identified nitro-ligand of RXRα. We hypothesized that Z-10 and its derivatives have the similar effect as bexarotene. A series of Z-10 derivatives were synthesized by introducing methoxyl, hydroxyl, and methoxy groups in 2- or 4-position of naphthalene ring, respectively. Our reporter gene assays showed that the derivatives with substituted groups of methyl and methoxyl in position 2 were more potent to activate Gal4-DBD/RXRα-LBD and RXRα homodimer as well as RXRα heterodimers than the corresponding 4-substituted derivatives. The derivatives with hydroxyl substitution in either 2- or 4-position failed to activate RXRα. Consistently, the derivatives with stronger potency of RXRα activation had higher RXRα binding affinity. Z-10 and its 2-ethyoxyl substituted derivative Z-36 reduced Aβ plaques in both hippocampus and cortex of AD mouse model significantly, of which Z-36 had stronger efficacy. This may due to the stronger ability of Z-36 than Z-10 in activating RXR/LXR and RXR/PPAR heterodimers and inducing ABCA1 and ABCG1 expressions. Thus, the 2- rather than 4-position was the better site for Z-10 modification as to RXRα transactivation, and Z-36 is an optimized derivative of Z-10 as to reducing Aβ plaques in AD mouse model.

中文翻译:

类视黄醇X受体Alpha硝基配体Z-10及其优化的衍生物Z-36减少阿尔茨海默氏病小鼠模型中的β-淀粉样蛋白斑块

已经证明,类视黄醇X受体α(RXRα)的激动剂贝沙罗汀通过激活RXR / LXR和RXR / PPAR异二聚体来增加apoE,ABCA1和ABCG1的表达,从而导致淀粉样蛋白β(Aβ)的蛋白质清除。阿尔茨海默氏病(AD)小鼠模型的大脑和小鼠认知缺陷的逆转。硝基苯乙烯衍生物Z-10是RXRα的第一个被鉴定的硝基配体。我们假设Z-10及其衍生物具有与贝沙罗汀相似的作用。通过分别在萘环的2或4位上引入甲氧基,羟基和甲氧基来合成一系列Z-10衍生物。我们的报告基因检测表明,与2位取代的衍生物相比,在2位带有甲基和甲氧基取代基的衍生物更有效地激活Gal4-DBD /RXRα-LBD和RXRα同二聚体以及RXRα异二聚体。在2位或4位羟基取代的衍生物无法激活RXRα。一致地,具有更强RXRα活化能力的衍生物具有更高的RXRα结合亲和力。Z-10及其2-乙氧基取代的衍生物Z-36可以显着降低AD小鼠模型海马和皮质的Aβ斑块,其中Z-36具有更强的功效。这可能是由于Z-36在激活RXR / LXR和RXR / PPAR异二聚体以及诱导ABCA1和ABCG1表达方面比Z-10具有更强的能力。因此,
更新日期:2018-07-11
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