H-TETRAZOL-5-YL)DECAHYDROISOQUINOLINE-3-CARBOXYLIC ACID, A NOVEL, COMPETITIVE, SYSTEMICALLY ACTIVE NMDA AND AMPA RECEPTOR ANTAGONIST

We report the synthesis and characterization of 6 (LY246492), which is a competitive N-methyl-D-aspartate (NMDA) and amino-3-(3-hydroxy-5-me thylisoxazol-4-yl)propanoic acid (AMPA) receptor antagonist. Tetrazole -substituted amino acid 6 was prepared in four steps from the recently described aldehyde 7. The optical isomers (-)-6 and (+)-6 were obtain ed from the same sequence of reactions using the corresponding isomers of 7. The compound displaces both NMDA and AMPA receptor binding and antagonizes depolarizations in cortical slices evoked by both NMDA and AMPA. In mice and pigeons, the compound showed antagonism of response s mediated through NMDA and AMPA receptors. Using the resolved optical isomers of 6, both NMDA and AMPA antagonist activities were found to reside in a single isomer, (-)-6.