Skolnick P, Marvizón J C, Jackson B W, Monn J A, Rice K C, Lewin A H
Laboratory of Neuroscience, NIDDK, National Institutes of Health, Bethesda, MD 20892.
Life Sci. 1989;45(18):1647-55. doi: 10.1016/0024-3205(89)90274-9.
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.
1-氨基环丙烷羧酸是N-甲基-D-天冬氨酸受体复合物上甘氨酸调节位点的一种强效且选择性的配体。该化合物以剂量依赖性方式阻断（半数有效剂量为234毫克/千克）N-甲基-D-天冬氨酸（125毫克/千克）所引起的惊厥和死亡。相比之下，1-氨基环丙烷羧酸不能保护小鼠免受戊四氮（80毫克/千克）、士的宁（2毫克/千克）、荷包牡丹碱（6毫克/千克）或最大电休克（50毫安，0.2秒）诱导的惊厥，并且在高达2克/千克的剂量下，对旋转棒或水平钢丝上的运动表现均无损害。1-氨基环丙烷羧酸的甲酯和乙酯在阻断N-甲基-D-天冬氨酸的惊厥和致死作用方面，分别比母体化合物强效5倍和2.3倍。然而，作为士的宁不敏感的[3H]甘氨酸结合抑制剂，这些酯的效力比1-氨基环丙烷羧酸低几个数量级（半数抑制浓度大于40微摩尔），这表明可能需要转化为母体化合物才能引发抗惊厥作用。这些发现表明，1-氨基环丙烷羧酸盐可能有助于治疗与N-甲基-D-天冬氨酸受体偶联阳离子通道过度激活相关的神经病理学。
