Wahl P, Frandsen A, Madsen U, Schousboe A, Krogsgaard-Larsen P
Department of Molecular Pharmacology, Novo Nordisk A/S, Måløv, Denmark.
Neuropharmacology. 1998 Oct-Nov;37(10-11):1205-10. doi: 10.1016/s0028-3908(98)00108-7.
(RS)-2-Amino-3-[3-(carboxymethoxy)-5-tert-butyl-4-isoxazolyl]propi onic acid (ATOA) has previously been described as an antagonist at (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors with an IC50 value of 150 microM towards AMPA-induced depolarisation in the rat cortical wedge preparation. ATOA has now been shown also to be a partial agonist at recombinant GluR5 receptors, expressed in Xenopus oocytes, with an EC50 value of 170 microM and a relative efficacy of 0.17 +/- 0.04 compared with responses produced by kainic acid (1.0). Using cultured cerebral cortical neurones as a test system and leakage of lactate dehydrogenase (LDH) as an indicator of cell damage, ATOA was shown to be cytotoxic (ED50 > 300 microM), though much less toxic than the structurally related dual AMPA and GluR5 agonist, (RS)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid (ATPA) (ED50 = 14 +/- 2 microM). The toxic effect of ATPA was sensitive to 6,7-dinitroquinoxaline-2,3-dione (DNQX) but was not significantly reduced by the selective AMPA receptor antagonist, (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA). The toxicity of ATOA (1 mM) could not be significantly attenuated by co-administration of AMOA (300 microM) or DNQX (25 microM). A structure-activity analysis indicates that the tert-butyl group of ATPA and ATOA facilitates the interaction of these compounds with GluR5 receptors.
（RS）-2-氨基-3-[3-（羧基甲氧基）-5-叔丁基-4-异恶唑基]丙酸（ATOA）先前已被描述为（RS）-2-氨基-3-（3-羟基-5-甲基-4-异恶唑基）丙酸（AMPA）受体的拮抗剂，在大鼠皮质楔形标本中，其对AMPA诱导的去极化的IC50值为150微摩尔。现已证明，ATOA在非洲爪蟾卵母细胞中表达的重组GluR5受体上也是部分激动剂，其EC50值为170微摩尔，与海藻酸（1.0）产生的反应相比，相对效能为0.17±0.04。以培养的大脑皮质神经元为测试系统，以乳酸脱氢酶（LDH）泄漏作为细胞损伤指标，结果表明ATOA具有细胞毒性（ED50>300微摩尔），尽管其毒性远低于结构相关的双AMPA和GluR5激动剂（RS）-2-氨基-3-（3-羟基-5-叔丁基-4-异恶唑基）丙酸（ATPA）（ED50=14±2微摩尔）。ATPA的毒性对6,7-二硝基喹喔啉-2,3-二酮（DNQX）敏感，但未被选择性AMPA受体拮抗剂（RS）-2-氨基-3-[3-（羧基甲氧基）-5-甲基-4-异恶唑基]丙酸（AMOA）显著降低。联合给予AMOA（300微摩尔）或DNQX（25微摩尔）不能显著减轻ATOA（1毫摩尔）的毒性。结构活性分析表明，ATPA和ATOA的叔丁基促进了这些化合物与GluR5受体的相互作用。
