Discovery of a Tamoxifen-Related Compound that Suppresses Glial L-Glutamate Transport Activity without Interaction with Estrogen Receptors

作者：Sato Kaoru^*; Kuriwaki Jun ichi; Takahashi Kanako; Saito Yoshihiko; Oka Jun ichiro; Otani Yuko; Sha Yu; Nakazawa Ken; Sekino Yuko; Ohwada Tomohiko

来源：ACS Chemical Neuroscience, 2012, 3(2): 105-113.

DOI：10.1021/cn200091w

• Tamoxifen
• astrocyte
• L-glutamate transporter
• ER alpha
• tetrasubstituted ethylene
• nongenomic pathway

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 beta-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.

• 出版日期2012-2