title: SPD 502: a water-soluble and in vivo long-lasting AMPA antagonist with neuroprotective activity.
abstract: 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]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-binding site (IC50 = 0.043 microM) compared with the [3H]kainate- (IC50 = 81 microM), [3H]cis-4-phosphonomethyl-2-piperidine carboxylic acid-(CGS 19755), and [3H]glycine-binding sites (IC50 > 30 microM) in rat cortical membranes. In an in vitro functional assay, SPD 502 blocked the AMPA-induced release of [3H]gamma-aminobutyric acid from cultured mouse cortical neurons in a competitive manner with an IC50 value of 0.23 microM. Furthermore, SPD 502 potently and selectively inhibited AMPA-induced currents in cortical neurons with an IC50 value of 0.15 microM. 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.
authors.affiliation: NeuroSearch A/S, Glostrup, Denmark. EON@NeuroSearch.dk
authors.forename: E O
authors.initials: EO
authors.lastname: Nielsen
authors.forename: T
authors.initials: T
authors.lastname: Varming
authors.forename: C
authors.initials: C
authors.lastname: Mathiesen
authors.forename: L H
authors.initials: LH
authors.lastname: Jensen
authors.forename: A
authors.initials: A
authors.lastname: Moller
authors.forename: A H
authors.initials: AH
authors.lastname: Gouliaev
authors.forename: F
authors.initials: F
authors.lastname: Wätjen
authors.forename: J
authors.initials: J
authors.lastname: Drejer
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000502:physiology*; D004597:Electroshock; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D007608:Kainic Acid / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010875:Pipecolic Acids / Q000493:pharmacokinetics; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000503:physiopathology / Q000517:prevention & control; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D018696:Neuroprotective Agents; D010875:Pipecolic Acids; D011758:Pyrroles; D011810:Quinoxalines; D018091:Receptors, AMPA; C119326:SPD 502; D044005:Tetrahydroisoquinolines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C053672:selfotel; D005680:gamma-Aminobutyric Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid; D005998:Glycine