SPD 502: A water-soluble and in vivo long-lasting AMPA antagonist with neuroprotective activity

Accumulating preclinical data suggest that compounds that block the excitat ory effect of glutamate on excitatory amino acid receptors may have neuropr otective effects and utility for the treatment of neurodegeneration after b rain ischemia. In the present study, the in vitro and in vivo pharmacologic al properties of the novel glutamate antagonist SPD 502 [8-methyl-5-(4-(N,N -dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinolin e-2,3-dione-3-O-(4-hydroxybutyric acid-2-yl)oxime] are described. In bindin g studies, SPD 502 was shown to display selectivity for the [H-3]alpha-amin o-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-binding site (IC50 = 0.043 mu M) compared with the [H-3]kainate- (IC50 = 81 mu M), [H-3]cis-4-ph osphonomethyl-2-piperidine carboxylic acid-(CGS 19755), and [H-3]glycine-bi nding sites (IC50 > 30 mu M) in rat cortical membranes. In an in vitro func tional assay, SPD 502 blocked the AMPA-induced release of [H-3]gamma-aminob utyric acid from cultured mouse cortical neurons in a competitive manner wi th an IC50 value of 0.23 mu M. Furthermore, SPD 502 potently and selectivel y inhibited AMPA-induced currents in cortical neurons with an IC50 value of 0.15 mu M. In in vivo electrophysiology, SPD 502 blocked AMPA-evoked spike activity in rat hippocampus after i.v. administration with an ED50 value o f 6.1 mg/kg and with a duration of action of more than 1 h. Furthermore, SP D 502 increased the seizure threshold for electroshock-induced tonic seizur es in mice at i.v doses of 40 mg/kg and higher. In the two-vessel occlusion model of transient forebrain ischemia in gerbils, SPD 502 (10 mg/kg bolus injection followed by a 10 mg/kg/h infusion for 2 h) resulted in a highly s ignificant protection against the ischemia-induced damage in the hippocampa l CA1 pyramidal neurons.