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
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.
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