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 lM, 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 lM, 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.

1-Substituted pyrazolo[1,5-c]quinazolines as novel Gly/NMDA receptor antagonists: synthesis, biological evaluation and molecular modeling study / F.VARANO; D. CATARZI; V. COLOTTA; F. R. CALABRI; O. LENZI; G. FILACCHIONI; A. GALLI; C. COSTAGLI; F. DEFLORIAN; S. MORO. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - STAMPA. - 13:(2005), pp. 5536-5549.

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

VARANO, FLAVIA;CATARZI, DANIELA;COLOTTA, VITTORIA;FILACCHIONI, GUIDO;GALLI, ALESSANDRO;
2005

Abstract

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 lM, 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 lM, 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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5536
5549
F.VARANO; D. CATARZI; V. COLOTTA; F. R. CALABRI; O. LENZI; G. FILACCHIONI; A. GALLI; C. COSTAGLI; F. DEFLORIAN; S. MORO
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/312957
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