Pure Appl. Chem., Vol. 76, No. 5, pp. 931–939, 2004. © 2004 IUPAC 931 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 1,‡ , G. De Sarro 2 , S. Quartarone 1 , M. L. Barreca 1 , R. Caruso 1 , L. De Luca 1 , and R. Gitto 1 1 Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata 98168, Messina, Italy; 2 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 com- putational studies which suggested the possible binding site for noncompetitive antagonists; we also developed a 3D ligand-based pharmacophore model in order to map common struc- tural 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 tetrahydroisoquino- line skeleton and led to the discovery of a very potent AMPAR antagonist with marked antiepileptic effects. INTRODUCTION Central nervous system (CNS) diseases are increasing, and there is a significant unmet medical need for new, effective, and safe drugs. There is considerable evidence that ion channel glutamate receptors (iGluRs), identified as NMDA, 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), and KA receptors, play important roles in a number of neurological disorders; consequently, they are potential targets for therapeutic intervention and ligands that interact with them are of significant inter- est. Considering the pivotal role of AMPA receptors (AMPARs) in physiological and pathological processes, significant effort has been focused on the synthesis of specific ligands as a source of poten- tial anticonvulsant and neuroprotective agents. In particular, the search was addressed in the field of noncompetitive antagonists because they do not bind at the same binding site of glutamate and there- fore remain efficacious independently of the level of the endogenous agonist reached during an ischem- ic or epileptic attack. Furthermore, their prolonged use in neuroprotective treatments might not influ- ence the normal glutamatergic activity [1]. *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. ‡ Corresponding author: E-mail: chimirri@pharma.unime.it