Blockade of N-methyl-D-aspartate induced convulsions by 1-aminocyclopropanecarboxylates.
1-Aminocyclopropanecarboxylic acid is a potent and selective ligand for the glycine modulatory site on the N-methyl-D-aspartate receptor complex. This compound blocks (ED50 234 mg/kg) the convulsions and deaths produced by N-methyl-D-aspartate (125 mg/kg) in a dose dependent fashion. In contrast, 1-aminocyclopropanecarboxylic acid does not protect mice against convulsions induced by pentylenetetrazole (80 mg/kg), strychnine (2 mg/kg), bicuculline (6 mg/kg), or maximal electroshock (50 mA, 0.2 s), and does not impair motor performance on either a rotarod or horizontal wire at doses of up to 2 g/kg. The methyl- and ethyl- esters of 1-aminocyclopropanecarboxylic acid are 5- and 2.3-fold more potent, respectively, than the parent compound in blocking the convulsant and lethal effects of N-methyl-D-aspartate. However, these esters are several orders of magnitude less potent (IC50 greater than 40 microM) than 1-aminocyclopropanecarboxylic acid as inhibitors of strychnine-insensitive [3H] glycine binding, indicating that conversion to the parent compound may be required to elicit an anticonvulsant action. These findings suggest that 1-aminocyclopropanecarboxylates may be useful in the treatment of neuropathologies associated with excessive activation of N-methyl-D-aspartate receptor coupled cation channels.
Skolnick
P
P
Laboratory of Neuroscience, NIDDK, National Institutes of Health, Bethesda, MD 20892.
Marvizón
J C
JC
Jackson
B W
BW
Monn
J A
JA
Rice
K C
KC
Lewin
A H
AH
D000596:Amino Acids / Q000494:pharmacology*; D000598:Amino Acids, Cyclic; D000818:Animals; D000927:Anticonvulsants; D001224:Aspartic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D001640:Bicuculline / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D008297:Male; D051379:Mice; D016202:N-Methylaspartate; D010433:Pentylenetetrazole / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013331:Strychnine / Q000378:metabolism / Q000633:toxicity; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism
D000596:Amino Acids; D000598:Amino Acids, Cyclic; D000927:Anticonvulsants; D001224:Aspartic Acid; C023863:1-aminocyclopropane-1-carboxylic acid; D016202:N-Methylaspartate; D013331:Strychnine; D010433:Pentylenetetrazole; D001640:Bicuculline