1-Substituted pyrazolo[1,5-c]quinazolines as novel Gly/NMDA receptor antagonists: Synthesis, biological evaluation, and molecular modeling study

A new set of 5,6-dihydro-pyrazolo[1,5-c]quinazoline-2-carboxylates (2–18), bearing different substituents (COOEt, Cl, Br, CH3, 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 (Ki = 0.18 and 0.16 μM, 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 (Ki = 0.09 and 0.059 μM, 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.

The synthesis and Gly/NMDA, AMPA, and KA receptor binding affinity of a new set of 5,6-dihydro-pyrazolo[1,5-c]quinazoline-2-carboxylates bearing different substituents at position-1 are described. A molecular modeling study has been carried out to better understand receptor affinity and selectivity of these new pyrazoloquinazoline derivatives.Figure optionsDownload as PowerPoint slide