YM90K - PHARMACOLOGICAL CHARACTERIZATION AS A SELECTIVE AND POTENT PHA-AMINO-3-HYDROXY-5-METHYLISOXAZOLE-4-PROPIONATE KAINATE RECEPTOR ANTAGONIST

We investigated the pharmacological properties and neuroprotective act ions of a novel pha-amino-3-hydroxy-5-methylisoxazole-y-propionate (AM PA)/kainate receptor antagonist, midazol-1-yl)-7-nitro-2,3-(1H,4H)-qui noxalinedione hydrochloride (YM90K); formerly YM900], in comparison wi th those of -dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX). YM90K selectively displaced [H-3]-AMPA binding (Ki = 0.084 mu M) and was less potent in inhibiting [H-3]-kainate (Ki = 2.2 mu M), [H-3]-L-g lutamate (N-methyl-D-aspartate-sensitive site; Ki > 100 mu M) and [H-3 ]-glycine (strychninine-insensitive site; Ki = 37 mu M) binding to rat brain membranes. YM90K co-injected with AMPA or kainate into the rat striatum protected cholinergic neurons against AMPA- or kainate-induce d neurotoxicity. YM90K showed potent suppressive activity against audi ogenic seizure in DBA/2 mice; ED(50) values of YM90K and NBQX against tonic seizure were 2.54 and 7.17 mg/kg (i.p.), respectively. The durat ion of the anticonvulsant effects of YM90K and NBQX was 30 min, indica ting that both compounds possess short action. In a global ischemia mo del, YM90K (15 mg/kg i.p. x 3), NBQX (30 mg/kg i.p. x 3) and CNQX (60 mg/kg i.p. x 3) significantly prevented the delayed neuronal death in the hippocampal CA1 region in Mongolian gerbils when administered 1 h after 5-min ischemia. In addition, the therapeutic time window for the neuroprotective effect of YM90K (30 mg/kg i.p. x 3) was 5 h. In a foc al ischemia model, YM90K (30 mg/kg i.v. bolus + 10 mg/kg/h for 4 h) re duced the volume of ischemic damage in the cerebral cortex in F344 rat s. Thus, YM90K was shown to be a potent and selective antagonist for A MPA/kainate receptors in vitro and in vivo. This compound may provide a therapeutic effect in various neurodegenerative disorders such as is chemic stroke in which glutamate neurotoxicity is thought to play a cr itical role in neuronal damage.