3-Hydroxy-1H-quinazoline-2,4-dione derivatives as new antagonists at ionotropic glutamate receptors: molecular modeling and pharmacological studies.
Based on our 3-hydroxy-7-chloroquinazoline-2,4-dione derivatives, previously reported as antagonists at ionotropic glutamate receptors, we synthesized new 3-hydroxyquinazoline-2,4-diones bearing a trifluoromethyl group at the 7-position and different groups at position 6. Glycine/NMDA, AMPA and kainate receptor binding data showed that the 7-trifluoromethyl residue increased AMPA and kainate receptor affinity and selectivity, with respect to the 7-chlorine atom. Among the probed 6-substituents, the 6-(1,2,4-triazol-4-yl) group (compound 8) was the most advantageous for AMPA receptor affinity and selectivity. Derivative 8 demonstrated to be effective in decreasing neuronal damage produced by oxygen and glucose deprivation in organotypic rat hippocampal slices and also showed anticonvulsant effects in pentylenetetrazole-induced convulsions. The previously reported kainate receptor antagonist 6-(2-carboxybenzoyl)-amino-7-chloro-3-hydroxyquinazoline-2,4-dione 3 prevented the failure of neurotransmission induced by oxygen and glucose deprivation in the CA1 region of rat hippocampal slices.
Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Universita' di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy. vittoria.colotta@unifi.it
Vittoria
V
Colotta
Ombretta
O
Lenzi
Daniela
D
Catarzi
Flavia
F
Varano
Lucia
L
Squarcialupi
Chiara
C
Costagli
Alessandro
A
Galli
Carla
C
Ghelardini
Anna Maria
AM
Pugliese
Giovanna
G
Maraula
Elisabetta
E
Coppi
Domenico E
DE
Pellegrini-Giampietro
Felicita
F
Pedata
Davide
D
Sabbadin
Stefano
S
Moro
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D010100:Oxygen / Q000378:metabolism; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000927:Anticonvulsants; D005947:Glucose; D010100:Oxygen; D052999:Quinazolinones; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors