Bioorganic and Medicinal Chemistry p. 5536 - 5549 (2005)
Update date:2022-08-03
Topics:
Varano, Flavia
Catarzi, Daniela
Colotta, Vittoria
Calabri, Francesca Romana
Lenzi, Ombretta
Filacchioni, Guido
Galli, Alessandro
Costagli, Chiara
Deflorian, Francesca
Moro, Stefano
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.
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Doi:10.1039/c6ob01683a
(2016)Doi:10.1016/j.poly.2005.04.023
(2005)Doi:10.1055/s-0039-1690130
(2019)Doi:10.1021/ol051096a
(2005)Doi:10.1021/ja042162r
(2005)Doi:10.1016/S0022-328X(00)81579-X
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