Preclinical anticonvulsant and neuroprotective profile of 8319, a non-competitive NMDA antagonist.

8319, ((+-)-2-Amino-N-ethyl-alpha-(3-methyl-2-thienyl)benzeneethanamine 2HCl), is a novel compound with the profile of a non-competitive NMDA antagonist. The compound displaced [3H] TCP with high affinity (IC50 = 43 nM), but was inactive at the NMDA, benzodiazepine and GABA sites; in vivo, 8319 showed good efficacy as an anticonvulsant and potential neuroprotective agent. It blocked seizures induced by NMDLA, supramaximal electroshock, pentylenetetrazol (PTZ), picrotoxin, and thiosemicarbazide with ED50's of 1-20 mg/kg ip. As a neuroprotective agent, 8319 (30-100 mg/kg sc) prevented the death of dorsal hippocampal pyramidal cells induced by direct injection of 20 nmol NMDA. At 15 mg/kg ip, the compound was also effective against hippocampal neuronal necrosis induced via bilateral occlusion of the carotid arteries in gerbils. In summary, 8319 is a noncompetitive NMDA antagonist with good anticonvulsant activity and may possess neuroprotective properties useful in the treatment of brain ischemia.
AuthorsS Fielding, J C Wilker, J Chernack, V Ramirez, C A Wilmot, L L Martin, J F Payack, M L Cornfeldt, K A Rudolphi, D K Rush
JournalProgress in clinical and biological research (Prog Clin Biol Res) Vol. 361 Pg. 533-41 ( 1990) ISSN: 0361-7742 [Print] UNITED STATES
PMID2290851 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Aniline Compounds
  • Anticonvulsants
  • Thiophenes
  • Tritium
  • compound 8319
  • N-Methylaspartate
  • Dizocilpine Maleate
  • Aniline Compounds (metabolism, pharmacology, therapeutic use)
  • Animals
  • Anticonvulsants (pharmacology, therapeutic use)
  • Binding, Competitive
  • Brain Diseases (prevention & control)
  • Brain Ischemia (drug therapy)
  • Dizocilpine Maleate (metabolism, pharmacology)
  • Gerbillinae
  • Hippocampus (drug effects)
  • Male
  • Mice
  • Mice, Inbred Strains
  • N-Methylaspartate (antagonists & inhibitors, toxicity)
  • Rats
  • Rats, Inbred Strains
  • Thiophenes (metabolism, pharmacology, therapeutic use)
  • Tritium

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