Vol. 289, Issue 3, 1492-1501, June 1999

SPD 502: A Water-Soluble and In Vivo Long-Lasting Ampa Antagonist with Neuroprotective Activity¹

Elsebet Ø. Nielsen, Thomas Varming, Claus Mathiesen, Leif H. Jensen, Arne Møller, Alex H. Gouliaev, Frank Wätjen and Jørgen Drejer

NeuroSearch A/S, Glostrup, Denmark

Accumulating preclinical data suggest that compounds that block the excitatory effect of glutamate on excitatory amino acid receptors may have neuroprotective effects and utility for the treatment of neurodegeneration after brain ischemia. In the present study, the in vitro and in vivo pharmacological 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]-isoquinoline-2,3-dione-3-O-(4-hydroxybutyric acid-2-yl)oxime] are described. In binding studies, SPD 502 was shown to display selectivity for the [³H]-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-binding site (IC₅₀ = 0.043 µM) compared with the [³H]kainate- (IC₅₀ = 81 µM), [³H]cis-4-phosphonomethyl-2-piperidine carboxylic acid-(CGS 19755), and [³H]glycine-binding sites (IC₅₀ > 30 µM) in rat cortical membranes. In an in vitro functional assay, SPD 502 blocked the AMPA-induced release of [³H]-aminobutyric acid from cultured mouse cortical neurons in a competitive manner with an IC₅₀ value of 0.23 µM. Furthermore, SPD 502 potently and selectively inhibited AMPA-induced currents in cortical neurons with an IC₅₀ value of 0.15 µM. In in vivo electrophysiology, SPD 502 blocked AMPA-evoked spike activity in rat hippocampus after i.v. administration with an ED₅₀ value of 6.1 mg/kg and with a duration of action of more than 1 h. Furthermore, SPD 502 increased the seizure threshold for electroshock-induced tonic seizures 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 significant protection against the ischemia-induced damage in the hippocampal CA1 pyramidal neurons.