Kawai M, Horikawa Y, Ishihara T, Shimamoto K, Ohfune Y
Suntory Institute for Biomedical Research, Osaka, Japan.
Eur J Pharmacol. 1992 Feb 11;211(2):195-202. doi: 10.1016/0014-2999(92)90529-d.
The excitatory actions of the eight stereoisomers of 2-(carboxycyclopropyl)glycine (CCG), conformationally rigid glutamate analogues, were analyzed for the glutamate receptor subtypes by means of binding assays with rat brain membranes. All CCG isomers inhibited the binding of [3H]3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid ([3H]CPP) to N-methyl-D-aspartate (NMDA) receptors. The (2S,3R,4S) isomer (L-CCG-IV) was the most potent agonist for the NMDA receptor and its binding potency was 17- and 790-fold higher than that of L-glutamate and NMDA, respectively. The (2S,3S,4R) isomer (L-CCG-III) showed a potent inhibitory activity for [3H]D-aspartate uptake. Further, L-CCG-IV caused a marked increase of intracellular free Ca2+ concentration [( Ca2+]i) and potent neurotoxicity in the single rat cerebral cortical neurons in vitro, and both were blocked effectively by the NMDA antagonists. Significant correlations were observed between neurotoxicity and the increase of [Ca2+]i and [3H]CPP binding affinity to the NMDA receptor.
通过与大鼠脑膜进行结合试验，分析了构象刚性谷氨酸类似物2 -（羧基环丙基）甘氨酸（CCG）的八种立体异构体对谷氨酸受体亚型的兴奋性作用。所有CCG异构体均抑制[³H]3 -（2 - 羧基哌嗪 - 4 - 基）丙基 - 1 - 膦酸（[³H]CPP）与N - 甲基 - D - 天冬氨酸（NMDA）受体的结合。（2S，3R，4S）异构体（L - CCG - IV）是NMDA受体最有效的激动剂，其结合效力分别比L - 谷氨酸和NMDA高17倍和790倍。（2S，3S，4R）异构体（L - CCG - III）对[³H]D - 天冬氨酸摄取表现出强效抑制活性。此外，L - CCG - IV在体外单个大鼠大脑皮质神经元中引起细胞内游离Ca²⁺浓度[（Ca²⁺]i）显著升高和强效神经毒性，且两者均被NMDA拮抗剂有效阻断。在神经毒性与[Ca²⁺]i升高以及[³H]CPP与NMDA受体的结合亲和力之间观察到显著相关性。
