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 μM) 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.