IN-VITRO AND IN-VIVO ANTAGONISM OF AMPA RECEPTOR ACTIVATION BY ZOLE-5-YL)ETHYL]DECAHYDROISOQUINOLINE-3-CARBOXYLIC ACID

The in vitro and in vivo pharmacology of a structurally novel competit ive antagonist for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole prop ionic acid (AMPA) subtype of excitatory amino acid receptors is descri bed. LY215490, azol-5-yl)ethyl)decahydroisoquinoline-3-carboxylic acid ), was shown to displace selectively H-3-AMPA and H-3-6-cyano-7-nitro- quinoxaline-2,3-dione (H-3-CNQX) binding to rat brain membranes. LY215 490 potently antagonized quisqualate-and AMPA- induced depolarizations of rat cortical slices in a competitive manner, while requiring highe r concentrations to antagonize the effects of N-methyl-D-aspartate (NM DA) and kainate. In slices of rat hippocampus, LY215490 also selective ly antagonized AMPA-evoked release of H-3-norepinephrine. These AMPA r eceptor activities were due to the(-) isomer of the compound, zole-5-y l)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558). LY215490 w as centrally active following parenteral administration in mice as dem onstrated by protection versus maximal electroshock seizures and decre ases in spontaneous motor activity. LY215490 (its active isomer being LY293558) represents a novel pharmacological agent for in vitro and in vivo studies of AMPA receptor function in the CNS.