BIOISOSTERICALLY MODIFIED DIPEPTIDE EXCITATORY AMINO-ACID RECEPTOR ANTAGONISTS CONTAINING 3-OXYGENATED ISOTHIAZOLE RING-SYSTEMS

The AMPA receptor agonist Thio-AMPA, the 3-isothiazolol analogue of AM PA was converted into the selective NMDA antagonist, 2, in which a 3-i sothiazolone unit is a bioisosteric analogue of the peptide bond of th e NMDA antagonist, gamma-(R)-Glu-Gly. The isomeric 3-oxygenated isothi azole amino acid, 3, and the corresponding isothiazole phosphono amino acid 4 were also synthesized, and were shown to be selective AMPA rec eptor antagonists. Compound 1, in which the peptide bond of gamma-(R)- Glu-Gly is replaced by an ester group, was synthesized and shown to be unstable in the test buffer system. (C) 1997 Elsevier Science Ltd.