Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity Relationship Study.
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 (IC5020 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.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
Stinne W
SW
Hansen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
Mette N
MN
Erichsen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
Bingru
B
Fu
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
Walden E
WE
Bjørn-Yoshimoto
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
Bjarke
B
Abrahamsen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
Jacob C
JC
Hansen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
Anders A
AA
Jensen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
Lennart
L
Bunch
D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology*; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D054879:Halogenation; D006801:Humans; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology
D001565:Benzoates; D027341:Excitatory Amino Acid Transporter 1; D005663:Furans; C493394:SLC1A3 protein, human; D053778:Thiazolidines