title: Synthesis, ionotropic glutamate receptor binding affinity, and structure-activity relationships of a new set of 4,5-dihydro-8-heteroaryl-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates analogues of TQX-173.
abstract: A series of 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates analogues of TQX-173 (1b), bearing different nitrogen-containing heterocycles at position-8, were synthesized as AMPA receptor antagonists. All the reported compounds were also biologically evaluated for their binding at glycine/NMDA and KA receptors to better assess their selectivity toward the AMPA receptor. Structure-activity relationships (SAR) on these TQX derivatives have evidenced that the precise positioning of the nitrogen atoms and the specific electronic topography of the 8-heteroaromatic ring are both important for the anchoring to the AMPA receptor. In fact, it has been well-established that the presence of a N(3)-nitrogen-containing heterocycle at position-8 of the TQX framework is an essential feature for potent and selective AMPA receptor antagonists. Functional antagonism at both AMPA receptor and NMDA receptor-ion channel complex was evaluated by assessing the ability of some selected compounds to inhibit depolarization induced by 5 microM AMPA or NMDA in mouse cortical wedge preparations.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via G. Capponi, 9, 50121 Firenze, Italy. daniela.catarzi@unifi.it
authors.forename: D
authors.initials: D
authors.lastname: Catarzi
authors.forename: V
authors.initials: V
authors.lastname: Colotta
authors.forename: F
authors.initials: F
authors.lastname: Varano
authors.forename: G
authors.initials: G
authors.lastname: Filacchioni
authors.forename: A
authors.initials: A
authors.lastname: Galli
authors.forename: C
authors.initials: C
authors.lastname: Costagli
authors.forename: V
authors.initials: V
authors.lastname: Carlà
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D016202:N-Methylaspartate; D011810:Quinoxalines; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D014227:Triazines; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C435935:TQX 173