Article

Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity Relationship Study.

Journal of Medicinal Chemistry, American Chemical Society (ACS), ISSN 0022-2623

Volume 59, 19, 2016

DOI:10.1021/acs.jmedchem.6b01058, Dimensions: pub.1055100341, PMID: 27626828,

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  1. (1) University of Copenhagen, grid.5254.6, KU

Countries

Denmark

Continents

Europe

Description

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.

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NORA University Profiles

University of Copenhagen

Danish Open Access Indicator

2016: Blocked

Research area: Medicine

Danish Bibliometrics Indicator

2016: Level 2

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 6

Field Citation Ratio (FCR): 1.82

Relative Citation ratio (RCR): 0.6