Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity Relationship Study
| Autor: | Walden E. Bjørn-Yoshimoto, Anders A. Jensen, Stinne W. Hansen, Lennart Bunch, Jacob C. Hansen, Bjarke Abrahamsen, Bingru Fu, Mette N. Erichsen |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Halogenation Stereochemistry Inhibitory postsynaptic potential 01 natural sciences Benzoates 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Structure–activity relationship Humans Furans IC50 Benzoic acid biology 010405 organic chemistry Excitatory amino-acid transporter Chemistry HEK 293 cells Transporter 0104 chemical sciences Excitatory Amino Acid Transporter 1 030104 developmental biology HEK293 Cells Biochemistry biology.protein Molecular Medicine Thiazolidines |
| Zdroj: | Journal of medicinal chemistry. 59(19) |
| ISSN: | 1520-4804 |
| Popis: | Screening of a small compound library at the three excitatory amino acid transporter subtypes 1-3 (EAAT1-3) resulted in the identification of compound (Z)-4-chloro-3-(5-((3-(2-ethoxy-2-oxoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid (1a) that exhibited a distinct preference as an inhibitor at EAAT1 (IC50 20 μM) compared to EAAT2 and EAAT3 (IC50 > 300 μM). This prompted us to subject 1a to an elaborate structure-activity relationship study through the purchase and synthesis and subsequent pharmacological characterization of a total of 36 analogues. Although this effort did not result in analogues with substantially improved inhibitory potencies at EAAT1 compared to that displayed by the hit, it provided a detailed insight into structural requirements for EAAT1 activity of this scaffold. The discovery of this new class of EAAT1-selective inhibitors not only supplements the currently available pharmacological tools in the EAAT field but also substantiates the notion that EAAT ligands not derived from α-amino acids hold considerable potential in terms of subtype-selective modulation of the transporters. |
| Databáze: | OpenAIRE |
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