Schoepp D D, Lodge D, Bleakman D, Leander J D, Tizzano J P, Wright R A, Palmer A J, Salhoff C R, Ornstein P L
Lilly Research Laboratory, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Neuropharmacology. 1995 Sep;34(9):1159-68. doi: 10.1016/0028-3908(95)00099-r.
The in vitro and in vivo pharmacology of a structurally novel competitive antagonist for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of excitatory amino acid receptors is described. LY215490, (+/-)(6-(2-(1-H-tetrazol-5-yl)ethyl) decahydroisoquinoline-3-carboxylic acid), was shown to displace selectively 3H-AMPA and 3H-6-cyano-7-nitro- quinoxaline-2,3-dione (3H-CNQX) binding to rat brain membranes. LY215490 potently antagonized quisqualate-and AMPA-induced depolarizations of rat cortical slices in a competitive manner, while requiring higher concentrations to antagonize the effects of N-methyl-D-aspartate (NMDA) and kainate. In slices of rat hippocampus, LY215490 also selectively antagonized AMPA-evoked release of 3H-norepinephrine. These AMPA receptor activities were due to the (-) isomer of the compound. (3S,4aR,6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl] decahydroisoquinoline-3-carboxylic acid (LY293558). LY215490 was centrally active following parenteral administration in mice as demonstrated by protection versus maximal electroshock seizures and decreases in spontaneous motor activity. LY215490 (its active isomer being LY293558) represents a novel pharmacological agent for in vitro and in vivo studies of AMPA receptor function in the CNS.
本文描述了一种结构新颖的、针对兴奋性氨基酸受体α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）亚型的竞争性拮抗剂的体外和体内药理学特性。LY215490，即（±）（6-（2-（1-H-四氮唑-5-基）乙基）十氢异喹啉-3-羧酸，已被证明能选择性地取代3H-AMPA和3H-6-氰基-7-硝基喹喔啉-2,3-二酮（3H-CNQX）与大鼠脑膜的结合。LY215490以竞争性方式强烈拮抗大鼠皮层切片中喹啉酸和AMPA诱导的去极化，而拮抗N-甲基-D-天冬氨酸（NMDA）和海人藻酸的作用则需要更高的浓度。在大鼠海马切片中，LY215490也能选择性地拮抗AMPA诱发的3H-去甲肾上腺素释放。这些AMPA受体活性归因于该化合物的（-）异构体，即（3S，4aR，6R，8aR）-6-[2-（1（2）H-四氮唑-5-基）乙基]十氢异喹啉-3-羧酸（LY293558）。经肠胃外给药后，LY215490在小鼠体内具有中枢活性，表现为对最大电休克惊厥的保护作用以及自发运动活性的降低。LY215490（其活性异构体为LY293558）是一种用于中枢神经系统中AMPA受体功能体外和体内研究的新型药理学试剂。
