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

Abstract

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.

• Authors: S 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
• Journal: Progress in clinical and biological research (Prog Clin Biol Res) Vol. 361 Pg. 533-41 ( 1990) ISSN: 0361-7742 [Print] United States
• PMID: 2290851 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Aniline Compounds
• Anticonvulsants
• Thiophenes
• Tritium
• compound 8319
• N-Methylaspartate
• Dizocilpine Maleate

Topics

• 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