title: Discovery of a Tamoxifen-related compound that suppresses glial l-glutamate transport activity without interaction with estrogen receptors.
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.
authors.affiliation: Laboratory of Neuropharmacology, Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. kasato@nihs.go.jp
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sato
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Kuriwaki
authors.forename: Kanako
authors.initials: K
authors.lastname: Takahashi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Oka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Otani
authors.forename: Yu
authors.initials: Y
authors.lastname: Sha
authors.forename: Ken
authors.initials: K
authors.lastname: Nakazawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekino
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohwada
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D055808:Drug Discovery; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors; D027342:Excitatory Amino Acid Transporter 2; D005110:Extracellular Space / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D018698:Glutamic Acid / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000819:agonists / Q000187:drug effects*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D018698:Glutamic Acid; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen; C493397:SLC1A2 protein, human; C493394:SLC1A3 protein, human