Inhibition of neuronal nitric oxide synthase activity by 3-[2-[4-(3-chloro-2-methylphenyl)- 1-piperazinyl]ethyl]-5, 6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel neuroprotective agent, in vitro and in cultured neuroblastoma cells in situ.
Inhibition of neuronal nitric oxide synthase activity by 3-[2-[4-(3-chloro-2-methylphenyl)- 1-piperazinyl]ethyl]-5, 6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel neuroprotective agent, in vitro and in cultured neuroblastoma cells in situ.
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DOI：
10.1016/s0006-2952(00)00370-1
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发表时间：
2000-09
影响因子：
5.8
通讯作者：
Kohji Fukunaga;Masao Ohmitsu;E. Miyamoto;Toshiyuki Sato;M. Sugimura;Toshihiro Uchida;Y. Shirasaki
中科院分区：
文献类型：
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作者：
Kohji Fukunaga;Masao Ohmitsu;E. Miyamoto;Toshiyuki Sato;M. Sugimura;Toshihiro Uchida;Y. Shirasaki
DY-9760e, 3-[2-[4-(3-氯-2-甲基苯基)-1-哌嗪基]乙基]-5,6-二甲氧基-1-(4-咪唑基甲基)-1H-吲唑二盐酸盐 3.5 水合物，一种新型钙调蛋白 (CaM) 拮抗剂，具有神经保护活性。在当前的研究中，我们检测了 DY-9760e 对体外一氧化氮合酶 (NOS) 活性以及对钙离子载体诱导的原位 NO 产生的影响。 DY-9760e 抑制神经元 NOS 和内皮 NOS 活性，而不影响诱导型 NOS 活性。它还抑制纯化的神经元 NOS 活性，其效力与体外纯化的 CaM 激酶 II 活性相似。此外，DY-9760e 在低于 1 μM 的浓度下可显着抑制小鼠 N1E-115 神经母细胞瘤细胞中 Ca2+ 离子载体 (A23187) 诱导的 NO 产生。相比之下，在培养的海马神经元中浓度高达 5 μM 时，没有观察到对 Ca2+/CaM 依赖性蛋白激酶 II 活性的明显抑制作用。这些结果表明 DY-9760e 对 CaM 依赖性 NOS 活性的抑制作用是该药物神经保护作用的基础。
DY-9760e, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, a novel calmodulin (CaM) antagonist, possesses neuroprotective activity. In the current study, we examined the effects of DY-9760e on nitric oxide synthase (NOS) activities in vitro and on calcium ionophore-induced NO production in situ. DY-9760e inhibited both neuronal NOS and endothelial NOS activities without affecting inducible NOS activity. It also inhibited purified neuronal NOS activity with a potency similar to that seen for purified CaM kinase II activity in vitro. Furthermore, DY-9760e significantly inhibited Ca2+ionophore (A23187)-induced NO production in mouse N1E-115 neuroblastoma cells, at a concentration of less than 1 μM. In contrast, no apparent inhibitory effect on Ca2+/CaM-dependent protein kinase II activity was observed in cultured hippocampal neurons up to 5 μM. These results suggest that the inhibitory effect of DY-9760e on CaM-dependent NOS activities underlies neuroprotective effects of the agent.