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

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...

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Bibliographic Details
Published in:Pure and applied chemistry 2004-01, Vol.76 (5), p.931-939
Main Authors: Chimirri, A., De Sarro, G., Quartarone, S., Barreca, M. L., Caruso, R., De Luca, L., Gitto, R.
Format: Article
Language:English
Subjects:
Binding sites
Computation
Ligands
Modulators
Neurological diseases
Organic chemistry
Pharmacology
Propionic acid
Three dimensional models
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Summary: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.
ISSN:0033-4545
1365-3075
DOI:10.1351/pac200476050931