title: Synthesis and preliminary evaluation of trans-3,4-conformationally-restricted glutamate and pyroglutamate analogues as novel EAAT2 inhibitors.
abstract: Select trans-4,5-[bi]cyclohexenylglutamic and pyroglutamic acids (3,4-substituted glutamates) were synthesized in three steps and were screened as potential inhibitors of the sodium dependent excitatory amino acid transporters 2 (EAAT2) and 3 (EAAT3), the chloride dependent glial cystine/glutamate exchanger system x(c)(-), and the glutamate vesicular transport system (VGLUT). Two glutamate analogues and one pyroglutamate analogue were found to inhibit EAAT2 with activity comparable to dihydrokainate.
authors.affiliation: Department of Chemistry, The University of Montana, Missoula, MT 59812 USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Denton
authors.forename: Todd
authors.initials: T
authors.lastname: Seib
authors.forename: Richard
authors.initials: R
authors.lastname: Bridges
authors.forename: Charles
authors.initials: C
authors.lastname: Thompson
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors; D027182:Amino Acid Transport System y+; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors*; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D005971:Glutamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D026901:Membrane Transport Proteins; D008958:Models, Molecular; D008968:Molecular Conformation; D011761:Pyrrolidonecarboxylic Acid / Q000138:chemical synthesis* / Q000494:pharmacology*; D027981:Symporters / Q000037:antagonists & inhibitors; D050598:Vesicular Glutamate Transport Protein 1; D033921:Vesicular Transport Proteins
chemical_list: D027322:Amino Acid Transport System X-AG; D027182:Amino Acid Transport System y+; D002352:Carrier Proteins; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D005971:Glutamates; D007202:Indicators and Reagents; D026901:Membrane Transport Proteins; C493464:SLC17A7 protein, human; C493400:SLC1A1 protein, human; C493397:SLC1A2 protein, human; C118895:SLC7A11 protein, human; D027981:Symporters; D050598:Vesicular Glutamate Transport Protein 1; D033921:Vesicular Transport Proteins; D011761:Pyrrolidonecarboxylic Acid