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.
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.
Colotta
Vittoria
V
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
Catarzi
Daniela
D
Varano
Flavia
F
Lenzi
Ombretta
O
Filacchioni
Guido
G
Costagli
Chiara
C
Galli
Alessandro
A
Ghelardini
Carla
C
Galeotti
Nicoletta
N
Gratteri
Paola
P
Sgrignani
Jacopo
J
Deflorian
Francesca
F
Moro
Stefano
S
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
D019342:Acetic Acid; D000700:Analgesics; D011799:Quinazolines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors