(4S)-4-amino-5,6-heptadienoic acid (MDL 72483): a potent anticonvulsant GABA-T inhibitor.

Abstract

(4S)-4-Amino-5,6-heptadienoic acid [S)-gamma-allenyl-GABA; MDL 72483) is a potent inactivator of brain GABA-T in mice; (ED50 (i.p.) = 60 mg.kg-1; ED50 (oral) = 70 mg.kg-1). Its anticonvulsant effects against 3-mercaptopropionic acid (MPA)-induced seizures in mice is related to the elevation of whole brain GABA concentrations: The mentioned doses of MDL 72483 which cause a decrease of GABA-T activity by 50%, produce within 5 h after dosing an increase of GABA concentration by about 3 mumol.g-1, and protect 50% of the mice against seizures in this model of presynaptic GABA deficit. When given orally MDL 72483 is about five times more potent than vigabatrin [4R/S)-4-amino-5-hexenoic acid) a known antiepileptic GABA-T inhibitor. Complete protection was achieved with a dose of 150 mg.kg-1. Similar to vigabatrin, MDL 72483 does not protect significantly against metrazol-induced convulsions. However, at a dose of 300 mg.kg-1, the time elapsing between metrazol administration and onset of convulsions was prolonged by a factor of 3.4. Oral administration of MDL 72483 for up to 19 days at a daily dose of 91-96 mg.kg-1 did not produce any obvious behavioral changes in mice, nor was the ED50 of the drug in MPA-seizure tests significantly altered by the pretreatment. These observations indicate that MDL 72483 is a promising drug for the treatment of certain epilepsies.

• Authors: S Sarhan, P Casara, B Knödgen, N Seiler
• Journal: Neurochemical research (Neurochem Res) Vol. 16 Issue 3 Pg. 285-93 (Mar 1991) ISSN: 0364-3190 [Print] United States
• PMID: 1780030 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Aminocaproates
• Anticonvulsants
• Fatty Acids, Unsaturated
• gamma-Aminobutyric Acid
• 4-amino-5,6-heptadienoic acid
• 3-Mercaptopropionic Acid
• 4-Aminobutyrate Transaminase
• Vigabatrin
• Pentylenetetrazole

Topics

• 3-Mercaptopropionic Acid
• 4-Aminobutyrate Transaminase (antagonists & inhibitors)
• Aminocaproates (administration & dosage, therapeutic use)
• Animals
• Anticonvulsants (therapeutic use)
• Fatty Acids, Unsaturated (administration & dosage, pharmacology, therapeutic use)
• Kinetics
• Male
• Mice
• Pentylenetetrazole
• Rats
• Rats, Inbred Strains
• Seizures (chemically induced, drug therapy, prevention & control)
• Vigabatrin
• gamma-Aminobutyric Acid (administration & dosage, analogs & derivatives, metabolism, pharmacology, therapeutic use)