Fuller R W, Hemrick-Luecke S K, Ornstein P L
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Neuropharmacology. 1992 Oct;31(10):1027-32. doi: 10.1016/0028-3908(92)90104-w.
LY274614, 3SR,4aRS,6SR,8aRS-6-[phosphonomethyl]decahydr oisoquinoline-3- carboxylic acid, has been described as a potent antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Here its ability to antagonize the prolonged depletion of dopamine in the striatum by amphetamine in iprindole-treated rats is reported. A single 18.4 mg/kg (i.p.) dose of (+/-)-amphetamine hemisulfate, given to rats pretreated with iprindole, resulted in persistent depletion of dopamine in the striatum 1 week later. This prolonged depletion of dopamine in the striatum was antagonized by dizocilpine (MK-801, a non-competitive antagonist of NMDA receptors) or by LY274614 (a competitive antagonist of NMDA receptors). The protective effect of LY274614 was dose-dependent, being maximum at 10-40 mgkg (i.p.). A 10 mg/kg dose of LY274614 was effective in antagonizing the depletion of dopamine in the striatum, when given as long as 8 hr prior to amphetamine but not when given 24 hr prior to amphetamine. Depletion of dopamine in the striatum was also antagonized when LY274614 was given after the injection of amphetamine; LY274614 protected when given up to 4 hr after but not when given 8 or 24 hr after amphetamine. The prolonged depletion of dopamine in the striatum in mice, given multiple injections of methamphetamine, was also antagonized dose-dependently and completely by LY274614. The data strengthen the evidence that the neurotoxic effect of amphetamine and related compounds toward nigrostriatal dopamine neurons involves NMDA receptors and that LY274614 is an NMDA receptor antagonist with long-lasting in vivo effects in rats.
LY274614，即3SR,4aRS,6SR,8aRS - 6 - [膦酰甲基]十氢异喹啉 - 3 - 羧酸，已被描述为谷氨酸受体N - 甲基 - D - 天冬氨酸（NMDA）亚型的强效拮抗剂。本文报道了其拮抗吲哚丙胺处理的大鼠纹状体中苯丙胺所致多巴胺长期耗竭的能力。给预先用吲哚丙胺处理的大鼠腹腔注射18.4 mg/kg（腹腔注射）的（±） - 苯丙胺半硫酸盐单次剂量，1周后导致纹状体中多巴胺持续耗竭。纹状体中多巴胺的这种长期耗竭可被地佐环平（MK - 801，一种NMDA受体的非竞争性拮抗剂）或LY274614（一种NMDA受体的竞争性拮抗剂）拮抗。LY274614的保护作用呈剂量依赖性，腹腔注射10 - 40 mg/kg时作用最强。10 mg/kg剂量的LY274614在苯丙胺给药前长达8小时给予时可有效拮抗纹状体中多巴胺的耗竭，但在苯丙胺给药前24小时给予则无效。当在注射苯丙胺后给予LY274614时，纹状体中多巴胺的耗竭也可被拮抗；在苯丙胺给药后4小时内给予LY274614可起到保护作用，但在苯丙胺给药后8小时或24小时给予则无效。多次注射甲基苯丙胺的小鼠纹状体中多巴胺的长期耗竭也可被LY274614剂量依赖性地完全拮抗。这些数据进一步证明，苯丙胺及相关化合物对黑质纹状体多巴胺能神经元的神经毒性作用涉及NMDA受体，且LY274614是一种在大鼠体内具有持久作用的NMDA受体拮抗剂。
