Schoepp D D, Salhoff C R, Fuson K S, Sacaan A I, Tizzano J P, Ornstein P L, May P C
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
J Neural Transm (Vienna). 1996;103(8-9):905-16. doi: 10.1007/BF01291781.
Glutamate receptor-mediated excitotoxicity is linked to the activation of multiple receptors including those activated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate. In this study, the novel glutamate receptor antagonist, as its active isomer (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahyd roisoquinoline-3- carboxylic acid ((-)LY293558) and it's +/- racemate (LY215490), was examined for neuroprotectant effects against excitotoxic injury in vitro and in vivo. This agent selectively protected against AMPA and kainate injury in cultured primary rat hippocampal neurons, an in vivo rat striatal neurotoxicity model, and against agonist-evoked seizures in mice. Thus, (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydr -oisguino-line-3-carboxylic acid represents a novel receptor selective and potent systemically active AMPA/kainate receptor antagonist for exploring neuroprotection via non-NMDA receptor mechanisms.
谷氨酸受体介导的兴奋性毒性与多种受体的激活有关，包括那些被α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）、N-甲基-D-天冬氨酸（NMDA）和海人藻酸激活的受体。在本研究中，对新型谷氨酸受体拮抗剂，即其活性异构体（3S,4aR,6R,8aR）-6-[2-(1(2)H-四唑-5-基)乙基]-十氢异喹啉-3-羧酸（（-）LY293558）及其±外消旋体（LY215490），进行了体外和体内抗兴奋性毒性损伤的神经保护作用研究。该药物在原代培养的大鼠海马神经元、体内大鼠纹状体神经毒性模型中对AMPA和海人藻酸损伤具有选择性保护作用，并对小鼠激动剂诱发的癫痫发作具有保护作用。因此，（3S,4aR,6R,8aR）-6-[2-(1(2)H-四唑-5-基)乙基]十氢异喹啉-3-羧酸是一种新型的受体选择性且全身活性的AMPA/海人藻酸受体拮抗剂，可用于通过非NMDA受体机制探索神经保护作用。
