title: Structural investigation of the 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione scaffold to obtain AMPA and kainate receptor selective antagonists. Synthesis, pharmacological, and molecular modeling studies.
abstract: In this paper, the study of new 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione derivatives, designed as AMPA and kainate (KA) receptor antagonists, is reported. Some derivatives bear different carboxy-containing alkyl chains on the 3-hydroxy group, while various heterocyclic rings or amide moieties are present at the 6-position of other compounds. Binding data at Gly/NMDA, AMPA, and high-affinity KA receptors showed that the presence of the free 3-hydroxy group is of paramount importance for a good affinity at all three investigated receptors, while introduction of some 6-heterocyclic moieties yielded AMPA-selective antagonists. The most significant result was the finding of the 6-(2-carboxybenzoylamino)-3-hydroxy-1H-quinazolin-2,4-dione 12, which possesses good affinity for high-affinity and low-affinity KA receptors (Ki=0.62 microM and 1.6 microM, respectively), as well as good selectivity. To rationalize the trend of affinities of the reported derivatives, an intensive molecular modeling study was carried out by docking compounds to models of the Gly/NMDA, AMPA, and KA receptors.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Polo Scientifico, Università degli Studi di Firenze, Sesto Fiorentino, (FI), Italy. vittoria.colotta@unifi.it
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.forename: Ombretta
authors.initials: O
authors.lastname: Lenzi
authors.forename: Guido
authors.initials: G
authors.lastname: Filacchioni
authors.forename: Chiara
authors.initials: C
authors.lastname: Costagli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Galli
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Galeotti
authors.forename: Paola
authors.initials: P
authors.lastname: Gratteri
authors.forename: Jacopo
authors.initials: J
authors.lastname: Sgrignani
authors.forename: Francesca
authors.initials: F
authors.lastname: Deflorian
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D019342:Acetic Acid; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004594:Electrophysiology; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019342:Acetic Acid; D000700:Analgesics; D011799:Quinazolines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors