3-alkyl GABA and 3-alkylglutamic acid analogues: two new classes of anticonvulsant agents.
Recently we showed that 3-alkyl-4-aminobutanoic acids are in vitro activators of brain L-glutamic acid decarboxylase (GAD) that show anticonvulsant activity. Since activation of GAD leads to increased concentrations of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in vitro, these compounds could represent a new class of anticonvulsant agents. Here it is shown that 3-alkylglutamic acid analogues also activate GAD and that all of the compounds in both series are active anticonvulsant agents against low intensity electroshock in mice. The most active compound, 3-isobutyl GABA, was tested further against maximal electroshock in mice and was shown to be very potent after both intravenous and oral administration without causing ataxia. It is not known if brain GABA levels are elevated in vivo by administration of these compounds or if the mechanism of anticonvulsant activity is related to their ability to activate GAD.
Taylor
C P
CP
Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert, Ann Arbor, MI 48105-2430.
Vartanian
M G
MG
Andruszkiewicz
R
R
Silverman
R B
RB
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004597:Electroshock; D004789:Enzyme Activation / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000378:metabolism; D005971:Glutamates / Q000494:pharmacology*; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D051379:Mice; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000927:Anticonvulsants; D005971:Glutamates; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase