Synthesis and biological evaluation of a new set of pyrazolo[1,5-c]quinazoline-2-carboxylates as novel excitatory amino acid antagonists.

Abstract

In recent papers (Catarzi, D.; et al. J. Med. Chem. 1999, 42, 2478-2484; 2000, 43, 3824-3826; 2001, 44, 3157-3165) we reported the synthesis of a set of 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQXs) that were active at the Gly/NMDA and/or AMPA receptors. In the present work the synthesis and Gly/NMDA, AMPA, and KA receptor binding affinities of a set of 5,6-dihydro-5-oxo-pyrazolo[1,5-c]quinazoline-2-carboxylates 1a,b-4a,b, 5a, 6a, and 7a,b-9a,b, (+/-)-5,6-dihydro-pyrazolo[1,5-c]quinazoline-2,5-dicarboxylates 10a,b and 11a,b, and (+/-)-1,5,6,10b-tetrahydro-5-oxo-pyrazolo[1,5-c]quinazoline-2-carboxylates 12a,b-14a,b are reported. The binding results indicate that compounds 1a,b-4a,b, 5a, 6a, and 7a,b-9a,b show good Gly/NMDA and/or AMPA receptor binding affinities, demonstrating that the pyrazoloquinazoline tricyclic system is an adequate alternative to the triazoloquinoxaline framework for anchoring at both receptor types. Moreover, the inactivity of the 2,5-dicarboxylate derivatives 10a,b and 11a,b at the Gly/NMDA and AMPA receptors indicates that the presence of a glycine moiety in the southern portion of the pyrazoloquinazoline framework is deleterious for receptor-ligand interaction. Finally, the binding data of compounds 12a,b-14a,b indicate that lack of planarity in the northeastern region of the molecules shifts selectivity toward the Gly/NMDA receptor, depending on the benzofused substitutions. In general, the pyrazoloquinazoline derivatives herein reported were inactive at the KA receptor. A study of the functional antagonism at both the AMPA receptor and the NMDA receptor-ion channel complex was also performed on some selected compounds.