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

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. 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 0.16 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 ( K i = 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.