title: (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.affiliation: Merrell Dow Research Institute, Strasbourg, France.
authors.forename: S
authors.initials: S
authors.lastname: Sarhan
authors.forename: P
authors.initials: P
authors.lastname: Casara
authors.forename: B
authors.initials: B
authors.lastname: Knödgen
authors.forename: N
authors.initials: N
authors.lastname: Seiler
mesh_terms: D015097:3-Mercaptopropionic Acid; D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000614:Aminocaproates / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007700:Kinetics; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000614:Aminocaproates; D000927:Anticonvulsants; D005231:Fatty Acids, Unsaturated; D005680:gamma-Aminobutyric Acid; C072694:4-amino-5,6-heptadienoic acid; D015097:3-Mercaptopropionic Acid; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin; D010433:Pentylenetetrazole