Novel AMPA and kainate receptor antagonists containing the pyrazolo[1,5-c]quinazoline ring system: Synthesis and structure-activity relationships.
This paper reports the synthesis and AMPA, Gly/NMDA, and KA receptor binding affinities of a new set of 1,9-disubstituted-8-chloro-pyrazolo[1,5-c]quinazoline-2-carboxylates 2-34. Binding data show that, in general, compounds 2-34 bind to the AMPA receptor with good affinity and selectivity. In particular, the obtained results indicate that the contemporary presence of a 1,2-dicarboxylic acid moiety and suitable benzo-substituents on the PQZ system is important to gain selective AMPA receptor antagonists. Moreover, this study shows that the presence of a 2-carboxybenzoylamino substituent at position-9 (compounds 33-34) is important for obtaining selective KA receptor antagonists. Some selected compounds were also tested for their functional antagonistic activity at both AMPA and NMDA receptor-ion channels.
Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Università degli Studi di Firenze, Polo Scientifico, via Ugo Schiff, 6, 50019 Sesto Fiorentino (FI), Italy.
Flavia
F
Varano
Daniela
D
Catarzi
Vittoria
V
Colotta
Ombretta
O
Lenzi
Guido
G
Filacchioni
Alessandro
A
Galli
Chiara
C
Costagli
D015394:Molecular Structure; D016202:N-Methylaspartate / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D016202:N-Methylaspartate; D011720:Pyrazoles; D011799:Quinazolines; D018092:Kainic Acid Receptors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C031280:pyrazole