Abstract:
: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.
journal_name
ACS Chem Neuroscijournal_title
ACS chemical neuroscienceauthors
Sato K,Kuriwaki J,Takahashi K,Saito Y,Oka J,Otani Y,Sha Y,Nakazawa K,Sekino Y,Ohwada Tdoi
10.1021/cn200091wsubject
Has Abstractpub_date
2012-02-15 00:00:00pages
105-13issue
2issn
1948-7193journal_volume
3pub_type
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