title: β-Sulfonamido Functionalized Aspartate Analogues as Excitatory Amino Acid Transporter Inhibitors: Distinct Subtype Selectivity Profiles Arising from Subtle Structural Differences.
abstract: In this study inspired by previous work on 3-substituted Asp analogues, we designed and synthesized a total of 32 β-sulfonamide Asp analogues and characterized their pharmacological properties at the excitatory amino acid transporter subtypes EAAT1, EAAT2, and EAAT3. In addition to several potent EAAT inhibitors displaying IC50values ∼1 μM at all three subtypes, this elaborate structure-activity relationship also identified analogues exhibiting distinct preferences or selectivities for specific transporter subtypes. Introduction of two fluorine atoms on the phenyl ring yielded analogue 4y that displayed an IC50of 0.8 μM at EAAT1 with a 14- and 9-fold preference over EAAT2 and EAAT3, respectively. Conversely, the m-CF3-phenyl analogue 4r was a potent selective EAAT2-inhibitor (IC50= 2.8 μM) exhibiting 30- and 50-fold selectivity over EAAT1 and EAAT3, respectively. In conclusion, even small structural differences in these β-sulfonamide Asp analogues provide analogues with diverse EAAT subtype selectivity profiles.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
authors.forename: Jacob C
authors.initials: JC
authors.lastname: Hansen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
authors.forename: Walden E
authors.initials: WE
authors.lastname: Bjørn-Yoshimoto
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Bisballe
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, Copenhagen Ø 2100, Denmark.
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
mesh_terms: D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; C493400:SLC1A1 protein, human; C493397:SLC1A2 protein, human; C493394:SLC1A3 protein, human; D013449:Sulfonamides; D001224:Aspartic Acid