A short and efficient synthesis of the selective human N-methyl-D-aspartate （NMDA） receptor 2A （NR2A） antagonist NVP-AAM077 is described. The target was achieved in 8 steps and in 54% overall yield from the commer...A short and efficient synthesis of the selective human N-methyl-D-aspartate （NMDA） receptor 2A （NR2A） antagonist NVP-AAM077 is described. The target was achieved in 8 steps and in 54% overall yield from the commercially available chemical 3-methylbenzene-1,2-diamine. A NaIO4/DMF-based oxidation of the bromide to corresponding aldehyde and an addition of phosphinic acid ester to the aldimine successfully served as the key steps.展开更多
Objectives:Duchenne muscular dystrophy(DMD)is characterized by the development of cardiac pathology secondarily expressed in mitochondrial dysfunction.DMD treatment includes support for mitochondrial function.The purp...Objectives:Duchenne muscular dystrophy(DMD)is characterized by the development of cardiac pathology secondarily expressed in mitochondrial dysfunction.DMD treatment includes support for mitochondrial function.The purpose of this work was to evaluate the effects of the lipophilic cation MKT-077,capable of modulating mitochondrial activity,on the structure and function of cardiac mitochondria in mdx and wild-type mice,as well as the state of this organ.Methods:Animals were divided into 4 groups:wild type(WT),WT+5 mg/kg MKT-077,mdx,mdx+5 mg/kg MKT-077.MKT-077 was administered intraperitoneally daily for 28 days.Finally,we assessed the parameters of the functioning of the cardiac mitochondria of mice,the expression of genes encoding proteins involved in mitochondrial communication,as well as the histology and ultrastructure of the myocardium and heart rate.Results:MKT-077 was shown to reverse mitochondrial hyperfunctionalization in mdx mice,reducing respiratory parameters to WT levels.MKT-077 also inhibited mitochondrial respiration in the hearts of WT mice.MKT-077 administration was accompanied by a tendency to normalize calcium retention capacity in the cardiac mitochondria of mdx mice.Myocardial ultrastructure and gene signature of mdx+MKT077 animals demonstrated increased mitophagy.We noted changes in the sarcoplasmic reticulum(SR)/mitochondria contacts,accompanied by differential changes in the level of genes encoding proteins involved in the communication of these organelles.This effect of MKT-077 was accompanied by normalization of the relative heart weight of mdx mice,a decrease in the level of fibrosis,and a tendency toward normalization of heart rate.Conclusion:MKT-077-induced reversal of cardiac mitochondrial hyperfunctionalization in mdx mice may promote a healthy-like state of the myocardium in these animals.展开更多
目的探讨N-甲基-D-天门冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR or NR)亚基NR2A在脑缺血再灌注引起的海马CA1区神经元树突棘丢失和认知功能障碍中的作用。方法制作三动脉阻断(3-VO)GFP转基因小鼠全脑缺血模型,小鼠随机分为假...目的探讨N-甲基-D-天门冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR or NR)亚基NR2A在脑缺血再灌注引起的海马CA1区神经元树突棘丢失和认知功能障碍中的作用。方法制作三动脉阻断(3-VO)GFP转基因小鼠全脑缺血模型,小鼠随机分为假手术组、脑缺血再灌注(I/R)组和NVP-AAM077(NVP)干预组;应用跳台试验测试小鼠学习记忆能力,激光共聚焦和Neurolucida软件分析检测海马CA1区神经元形态及树突棘的变化。结果学习记忆能力测试发现,I/R组明显差于sham组(P<0.05),NVP干预组差于sham组和I/R组(P<0.05);I/R组CA1区神经元树突棘的数量明显少于假手术组(P<0.01),NVP干预能进一步增加缺血/再灌注所致的CA1区神经元树突棘的丢失(P<0.05)。结论 NMDA受体亚基NR2A在小鼠脑缺血再灌注所致树突棘丢失和脑认知功能损害中具有重要作用。展开更多
Cortical spreading depression (CSD) is a transient synaptic excitation, followed by depression, which can propagate slowly across cortex, subcortex and retina. CSD is implicated in migraine with aura and may lead to m...Cortical spreading depression (CSD) is a transient synaptic excitation, followed by depression, which can propagate slowly across cortex, subcortex and retina. CSD is implicated in migraine with aura and may lead to migraine pain. CSD can be suppressed by inhibition of both NR2A and NR2B containing N-methyl-D-aspartic acid (NMDA) receptors. However, whether there is a synergistic effect of co-inhibition of NR2A and NR2B containing receptors on CSD remains unknown. In this study, an efficient in vitro model of migraine with intrinsic optical imaging approach was applied to address this role of co-activation of both NR2A and NR2B in CSD. The results showed that co-application of NVP-AAM077, a drug selectively targeting for NR2A and Ro 25-6981, a drug selectively targeting for NR2B containing receptors, showed synergistic inhibitory effects on propagation rate and the magnitude of CSD in a concentration dependent manner in chick retina. Inhibition of CSD propagation was also observed by a clinical acceptable drug that antagonizes both NR2A and NR2B containing receptors, memantine, at 10 μM. These data suggest that combinational use of antagonists selectively targeting NR2A and NR2B containing receptors could be a useful strategy for preventative treatment of migraine with improved efficacy with potential alleviated side effects.展开更多
基金Project supported by the Natural Science Foundation of China （Nos. 20425205, 20321202）, Chinese Academy of Sciences （No. KGCX2-SW-209） and Shanghai Municipal Commission of Science and Technology （No. 04DZ14901）.
文摘A short and efficient synthesis of the selective human N-methyl-D-aspartate （NMDA） receptor 2A （NR2A） antagonist NVP-AAM077 is described. The target was achieved in 8 steps and in 54% overall yield from the commercially available chemical 3-methylbenzene-1,2-diamine. A NaIO4/DMF-based oxidation of the bromide to corresponding aldehyde and an addition of phosphinic acid ester to the aldimine successfully served as the key steps.
基金supported by a grant from the Russian Science Foundation(23-75-10006).
文摘Objectives:Duchenne muscular dystrophy(DMD)is characterized by the development of cardiac pathology secondarily expressed in mitochondrial dysfunction.DMD treatment includes support for mitochondrial function.The purpose of this work was to evaluate the effects of the lipophilic cation MKT-077,capable of modulating mitochondrial activity,on the structure and function of cardiac mitochondria in mdx and wild-type mice,as well as the state of this organ.Methods:Animals were divided into 4 groups:wild type(WT),WT+5 mg/kg MKT-077,mdx,mdx+5 mg/kg MKT-077.MKT-077 was administered intraperitoneally daily for 28 days.Finally,we assessed the parameters of the functioning of the cardiac mitochondria of mice,the expression of genes encoding proteins involved in mitochondrial communication,as well as the histology and ultrastructure of the myocardium and heart rate.Results:MKT-077 was shown to reverse mitochondrial hyperfunctionalization in mdx mice,reducing respiratory parameters to WT levels.MKT-077 also inhibited mitochondrial respiration in the hearts of WT mice.MKT-077 administration was accompanied by a tendency to normalize calcium retention capacity in the cardiac mitochondria of mdx mice.Myocardial ultrastructure and gene signature of mdx+MKT077 animals demonstrated increased mitophagy.We noted changes in the sarcoplasmic reticulum(SR)/mitochondria contacts,accompanied by differential changes in the level of genes encoding proteins involved in the communication of these organelles.This effect of MKT-077 was accompanied by normalization of the relative heart weight of mdx mice,a decrease in the level of fibrosis,and a tendency toward normalization of heart rate.Conclusion:MKT-077-induced reversal of cardiac mitochondrial hyperfunctionalization in mdx mice may promote a healthy-like state of the myocardium in these animals.
文摘目的探讨N-甲基-D-天门冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR or NR)亚基NR2A在脑缺血再灌注引起的海马CA1区神经元树突棘丢失和认知功能障碍中的作用。方法制作三动脉阻断(3-VO)GFP转基因小鼠全脑缺血模型,小鼠随机分为假手术组、脑缺血再灌注(I/R)组和NVP-AAM077(NVP)干预组;应用跳台试验测试小鼠学习记忆能力,激光共聚焦和Neurolucida软件分析检测海马CA1区神经元形态及树突棘的变化。结果学习记忆能力测试发现,I/R组明显差于sham组(P<0.05),NVP干预组差于sham组和I/R组(P<0.05);I/R组CA1区神经元树突棘的数量明显少于假手术组(P<0.01),NVP干预能进一步增加缺血/再灌注所致的CA1区神经元树突棘的丢失(P<0.05)。结论 NMDA受体亚基NR2A在小鼠脑缺血再灌注所致树突棘丢失和脑认知功能损害中具有重要作用。
文摘Cortical spreading depression (CSD) is a transient synaptic excitation, followed by depression, which can propagate slowly across cortex, subcortex and retina. CSD is implicated in migraine with aura and may lead to migraine pain. CSD can be suppressed by inhibition of both NR2A and NR2B containing N-methyl-D-aspartic acid (NMDA) receptors. However, whether there is a synergistic effect of co-inhibition of NR2A and NR2B containing receptors on CSD remains unknown. In this study, an efficient in vitro model of migraine with intrinsic optical imaging approach was applied to address this role of co-activation of both NR2A and NR2B in CSD. The results showed that co-application of NVP-AAM077, a drug selectively targeting for NR2A and Ro 25-6981, a drug selectively targeting for NR2B containing receptors, showed synergistic inhibitory effects on propagation rate and the magnitude of CSD in a concentration dependent manner in chick retina. Inhibition of CSD propagation was also observed by a clinical acceptable drug that antagonizes both NR2A and NR2B containing receptors, memantine, at 10 μM. These data suggest that combinational use of antagonists selectively targeting NR2A and NR2B containing receptors could be a useful strategy for preventative treatment of migraine with improved efficacy with potential alleviated side effects.
