title: 1-Substituted pyrazolo[1,5-c]quinazolines as novel Gly/NMDA receptor antagonists: synthesis, biological evaluation, and molecular modeling study.
abstract: A new set of 5,6-dihydro-pyrazolo[1,5-c]quinazoline-2-carboxylates (2-18), bearing different substituents (COOEt, Cl, Br, CH(3), and COOH) at position-1, were synthesized in order to investigate the influence of various groups at this specific position on Gly/NMDA receptor affinity and/or selectivity. All the herein reported compounds were evaluated for their binding at the Gly/NMDA, AMPA, and KA receptors. Some selected compounds were also tested for their functional antagonistic activity at both the AMPA and NMDA receptor-ion channels. The results obtained in this study have highlighted that a C-1 lipophilic substituent on the pyrazolo[1,5-c]quinazoline-2-carboxylate core shifts selectivity toward the Gly/NMDA receptor, while a C-1 anionic carboxylate residue is able to increase affinity toward this receptor subtype. In particular, the 2-carboxylic acids 15 and 16, bearing a chlorine atom at position-1, are not only potent (K(i)=0.18 and 0.16muM, respectively), but also highly Gly/NMDA versus AMPA selective (selectivity ratio>500). Furthermore, the 1,2-dicarboxylic acids 13 and 14 are endowed with the highest Gly/NMDA receptor binding activity (K(i)=0.09 and 0.059muM, respectively), among the pyrazoloquinazoline series of derivatives. A molecular modeling study has been carried out to better understand receptor affinity and selectivity of these new pyrazoloquinazoline derivatives.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Polo Scientifico, via Ugo Schiff, 6, 50019 Sesto Fiorentino (FI), Italy. flavia.varano@unifi.it
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Calabri
authors.forename: Ombretta
authors.initials: O
authors.lastname: Lenzi
authors.forename: Guido
authors.initials: G
authors.lastname: Filacchioni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Galli
authors.forename: Chiara
authors.initials: C
authors.lastname: Costagli
authors.forename: Francesca
authors.initials: F
authors.lastname: Deflorian
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011720:Pyrazoles; D011799:Quinazolines; D016194:Receptors, N-Methyl-D-Aspartate