jm6b01058_si_001.csv (3.68 kB)
Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure–Activity Relationship Study
dataset
posted on 2016-09-14, 20:23 authored by Stinne
W. Hansen, Mette N. Erichsen, Bingru Fu, Walden E. Bjørn-Yoshimoto, Bjarke Abrahamsen, Jacob
C. Hansen, Anders A. Jensen, Lennart BunchScreening 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.