The effects of D-23129, a new experimental anticonvulsant drug, on neurotransmitter amino acids in the rat hippocampus in vitro.
D-23129 [N-(2-amino-4-(4-fluorobenzylamino)phenyl)carbamic acid ethyl ester] and D-20443 (dihydrochloride of D-23129) are promising anticonvulsant compounds with a broad spectrum activity in animal models of epilepsy. Their effects on de novo synthesis of excitatory (glutamate and aspartate) and inhibitory (GABA) amino acids were studied in rat hippocampal slices. Like phenytoin, carbamazepine, lamotrigine, losigamone, U54494A, and flupirtine, D-23129 and D-20443 were effective in preventing the effects of a chemoconvulsant, 4-aminopyridine, on de novo synthesis of the three amino acids. However, unlike the other compounds, D-23129 and D-20443 also preferentially increased the concentrations of newly synthesized GABA. Their effect on the neosynthesis of GABA was unique, dose dependent, and not tetrodotoxin sensitive. A total of 15 compounds (including standard, new and candidate anticonvulsants) either had no effect on new GABA or decreased it. Therefore, D-23129 and D-20443 exhibited two different effects on de novo synthesis of neurotransmitter amino acids, both of which could potentially be anticonvulsant in nature.
Kapetanovic
I M
IM
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. imkap@helix.nih.gov
Yonekawa
W D
WD
Kupferberg
H J
HJ
D015761:4-Aminopyridine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000096:biosynthesis; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D010655:Phenylenediamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis
D000927:Anticonvulsants; D002219:Carbamates; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D010655:Phenylenediamines; C101866:ezogabine; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D015761:4-Aminopyridine