Laboratory of Neuropharmacology, Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
ACS Chem Neurosci. 2012 Feb 15;3(2):105-13. doi: 10.1021/cn200091w. Epub 2011 Nov 14.
We recently found that tamoxifen suppresses l-glutamate transport activity of cultured astrocytes. Here, in an attempt to separate the l-glutamate transporter-inhibitory activity from the estrogen receptor-mediated genomic effects, we synthesized several compounds structurally related to tamoxifen. Among them, we identified two compounds, 1 (YAK01) and 3 (YAK037), which potently inhibited l-glutamate transporter activity. The inhibitory effect of 1 was found to be mediated through estrogen receptors and the mitogen-activated protein kinase (MAPK)/phosphatidylinositol 3-kinase (PI3K) pathway, though 1 showed greatly reduced transactivation activity compared with that of 17β-estradiol. On the other hand, compound 3 exerted its inhibitory effect through an estrogen receptor-independent and MAPK-independent, but PI3K-dependent pathway, and showed no transactivation activity. Compound 3 may represent a new platform for developing novel l-glutamate transporter inhibitors with higher brain transfer rates and reduced adverse effects.
我们最近发现他莫昔芬抑制培养的星形胶质细胞中 l-谷氨酸的转运活性。在这里，为了将 l-谷氨酸转运体抑制活性与雌激素受体介导的基因组效应分开，我们合成了几种与他莫昔芬结构相关的化合物。其中，我们鉴定出两种化合物 1（YAK01）和 3（YAK037），它们强烈抑制 l-谷氨酸转运体活性。发现 1 的抑制作用是通过雌激素受体和丝裂原活化蛋白激酶（MAPK）/磷酸肌醇 3-激酶（PI3K）途径介导的，尽管 1 的转录激活活性与 17β-雌二醇相比大大降低。另一方面，化合物 3 通过雌激素受体非依赖性和 MAPK 非依赖性但 PI3K 依赖性途径发挥其抑制作用，并且没有转录激活活性。化合物 3 可能代表开发具有更高脑转移率和减少不良反应的新型 l-谷氨酸转运体抑制剂的新平台。
