Neuroprotective effects of RPR 104632, a novel antagonist at the glycine site of the NMDA receptor, in vitro
Neuroprotective effects of RPR 104632, a novel antagonist at the glycine site of the NMDA receptor, in vitro
复制标题
DOI：
10.1016/0014-2999(95)00780-6
复制
发表时间：
1996-04-11
影响因子：
5
通讯作者：
Doble, A
中科院分区：
文献类型：
--
作者：
Boireau, A;Malgouris, C;Doble, A
描述了RPR 104632（2 H-1，2，4-苯并噻二嗪-1-二氧化物-3-羧酸）的NMDA拮抗剂和神经保护作用，RPR 104632是一种新型苯并噻二嗪衍生物，对NMDA受体-通道复合物的甘氨酸位点具有亲和力。RPR 104632拮抗[H-3] 5，7-二氯犬尿烯酸与大鼠大脑皮层的结合，Ki为4.9 nM。这种效应是立体特异性的，因为（-）-异构体的效力比（+）-异构体高500倍。通过观察到RPR 104632在存在N-甲基-D-天冬氨酸（NMDA）的情况下抑制[H-3]N-[1-（2-噻吩基）环己基]-3，4-哌啶（[H-3]TCP）结合（IC 50 = 55 nM），而对竞争性NMDA位点或解离性麻醉位点无影响，证实了RPR 104632对甘氨酸位点的强效亲和力。RPR 104632以非竞争性方式抑制NMDA诱导的新生大鼠小脑切片中鸟苷3 '，5'-环磷酸（cGMP）水平升高（IC 50 = 890 nM），并显著降低大鼠海马切片和皮质原代细胞培养物中NMDA诱导的神经毒性。这些结果表明，RPR 104632是一种与NMDA受体通道偶联的甘氨酸位点的高亲和力特异性拮抗剂，在体外具有强效神经保护特性。
The NMDA antagonist and neuroprotective effects of RPR 104632 (2H-1,2,4-benzothiadiazine-1-dioxide-3-carboxylic acid), a new benzothiadiazine derivative, with affinity for the glycine site of the NMDA receptor-channel complex are described. RPR 104632 antagonized the binding of [H-3]5,7-dichlorokynurenic acid to the rat cerebral cortex, with a K-i of 4.9 nM. This effect was stereospecific, since the (-)-isomer was 500-fold more potent than the (+)-isomer. The potent affinity of RPR 104632 for the glycine site was confirmed by the observation that RPR 104632 inhibited [H-3]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine ([H-3]TCP) binding in the presence of N-methyl-D-aspartate (NMDA) (IC50 = 55 nM), whereas it had no effect on the competitive NMDA site or on the dissociative anaesthetic site. RPR 104632 inhibited the NMDA-evoked increase in guanosine 3',5'-cyclic monophosphate (cGMP) levels of neonatal rat cerebellar slices (IC50 = 890 nM) in a non-competitive manner and markedly reduced NMDA-induced neurotoxicity in rat hippocampal slices and in cortical primary cell cultures. These results suggest that RPR 104632 is a high-affinity specific antagonist of the glycine site coupled to the NMDA receptor channel with potent neuroprotective properties in vitro.