Synthesis and pharmacological studies at the Gly/NMDA, AMPA and Kainate receptors of new oxazolo[4,5-c]quinolin-4-one derivatives bearing different substituents at position-2 and on the fused benzo ring.
The synthesis and biological evaluation at the Gly/NMDA, AMPA and Kainate receptors of new oxazolo[4,5-c]quinolin-4-one derivatives are reported. Different substituents were introduced at the 2-position (mercapto, carbonyl and methyl groups) and on the fused benzo ring (chlorine atom(s) and trifluoromethyl group). Among the herein reported compounds, the 2-mercapto-derivatives 1-4 showed the highest Gly/NMDA affinities, comparable to that of 5,7-dichlorokynurenic acid. The most active compound was the 7-chloro-substituted derivative 1 (Ki=0.082 microM) which possesses a Gly/NMDA selectivity of 50- and 500-fold with respect to AMPA and KA receptors, respectively. Functional antagonism studies performed on some selected 2-mercapto compounds, at both AMPA and NMDA receptor-ion channels, assessed the antagonistic properties of these derivatives. SAR studies pointed out the importance of the concurrent presence of electron-rich moieties at both the 2- and 3-positions of the oxazolo[4,5-c]quinolin-4-one framework. In fact, the 3-sp2-nitrogen atom plays a significant role in reinforcing the hydrogen bond that the 4-carbonyl oxygen probably forms with the arginine residue (R523) of the Gly/NMDA receptor site. The presence of 2-substituent able to form a hydrogen bonding interaction was also proved to be important for a good Gly/NMDA receptor affinity.
Calabri
Francesca Romana
FR
Dipartimento di Scienze Farmaceutiche, Universita' degli Studi di Firenze, Polo Scientifico, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, FI, Italy.
Colotta
Vittoria
V
Catarzi
Daniela
D
Varano
Flavia
F
Lenzi
Ombretta
O
Filacchioni
Guido
G
Costagli
Chiara
C
Galli
Alessandro
A
D000465:Algorithms; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000737:chemistry; D017470:Receptors, Glutamate / Q000737:chemistry / Q000187:drug effects*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
D018691:Excitatory Amino Acid Antagonists; D006575:Heterocyclic Compounds, 3-Ring; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate