title: Synthesis and biological evaluation of novel 9-heteroaryl substituted 7-chloro-4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQX) as (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists.
abstract: In this paper, we report a study on some new 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylate derivatives (TQXs), bearing a nitrogen-containing heterocycle at position-9, and designed as (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists. These compounds ensue from the structural modification of previously reported 8-heteroaryl-TQXs which were endowed with high affinity and selectivity for the AMPA receptor. All the newly synthesized compounds were biologically evaluated for their binding at the AMPA receptor. Gly/N-methyl-D-aspartic acid (NMDA) and kainic acid (KA) high-affinity binding assays were performed to assess the selectivity of the reported derivatives toward the AMPA receptor. This study produced some new TQXs which are less potent than the reference compounds, and endowed with a mixed AMPA and Gly/NMDA receptor binding affinity. To rationalize the experimental findings, a molecular modeling study was performed by docking some TQX derivatives to the AMPA receptor model.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Universita' degli Studi di Firenze, Sesto Fiorentino, Italy. daniela.catarzi@unifi.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.forename: Guido
authors.initials: G
authors.lastname: Filacchioni
authors.forename: Paola
authors.initials: P
authors.lastname: Gratteri
authors.forename: Jacopo
authors.initials: J
authors.lastname: Sgrignani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Galli
authors.forename: Chiara
authors.initials: C
authors.lastname: Costagli
mesh_terms: D008968:Molecular Conformation; D015394:Molecular Structure; D011422:Propionates / Q000378:metabolism; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
chemical_list: D011422:Propionates; D011810:Quinoxalines; D018091:Receptors, AMPA; C435935:TQX 173; D014227:Triazines; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C029658:propionic acid