Discovery of a Tamoxifen-Related Compound that Suppresses Glial l-Glutamate Transport Activity without Interaction with Estrogen Receptors
详细信息 查看全文
- 作者：Kaoru Sato ; Jun-ichi Kuriwaki ; Kanako Takahashi ; Yoshihiko Saito ; Jun-ichiro Oka ; Yuko Otani ; Yu Sha ; Ken Nakazawa ; Yuko Sekino ; Tomohiko Ohwada
- 刊名：ACS Chemical Neuroscience
- 出版年：2012
- 出版时间：February 15, 2012
- 年：2012
- 卷：3
- 期：2
- 页码：105-113
- 全文大小：492K
- 年卷期：v.3,no.2(February 15, 2012)
- ISSN：1948-7193
文摘
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 17尾-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.