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Pure Appl. Chem. 76(5), 931-939, 2004

Pure and Applied Chemistry

Vol. 76, Issue 5

Search for noncompetitive 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid receptor (AMPAR) antagonists: Synthesis, pharmacological properties, and computational studies

A. Chimirri, G. De Sarro, S. Quartarone, M. L. Barreca, R. Caruso, L. De Luca, and R. Gitto

Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata 98168, Messina, Italy; Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro, Italy

Abstract: The development of new 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor (AMPAR) negative modulators has received considerable interest due
to their crucial role in specific neurological diseases.
In recent years, our research group has been engaged in the development of new AMPAR ligands and chemical and biological studies of various 2,3-benzodiazepin-4-(thi)ones (CFMs) and their analogous cyclofunctionalized have been reported. Electrophysiological experiments confirmed that their effects are mediated through the AMPAR complex in a selective and noncompetitive fashion. Moreover, we carried out computational studies which suggested the possible binding site for noncompetitive antagonists; we also developed a 3D ligand-based pharmacophore model in order to map common structural features of highly potent compounds. Our hypothesis was successfully used as a frame-
work for the design of a new class of allosteric modulators containing a tetrahydroisoquinoline skeleton and led to the discovery of a very potent AMPAR antagonist with marked antiepileptic effects.

*Lecture presented at the Polish-Austrian-German-Hungarian-Italian Joint Meeting on Medicinal Chemistry, Kraków, Poland, 15-18 October 2003. Other presentations are published in this issue, pp. 907 -1032.

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