O'Neill M J, Bond A, Ornstein P L, Ward M A, Hicks C A, Hoo K, Bleakman D, Lodge D
Lilly Research Centre, Eli Lilly and Co. Ltd., Windlesham, UK.
Neuropharmacology. 1998 Oct-Nov;37(10-11):1211-22. doi: 10.1016/s0028-3908(98)00134-8.
In the present studies, we have evaluated the activity of a series of glutamate receptor antagonists from the decahydroisoquinoline group of compounds both in vitro and in vivo. Compound activity at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors was assessed using ligand binding to cloned iGluR2 and iGluR5 receptors and on responses evoked by AMPA and N-methyl-D-aspartate (NMDA) in the cortical wedge preparation. In vivo, compounds were examined for antagonist activity electrophysiologically in the rat spinal cord preparation and in the gerbil model of global cerebral ischaemia. Compounds tested were LY293558, which has been shown to protect in models of focal cerebral ischaemia, LY202157 (an NMDA antagonist), LY246492 (an NMDA and AMPA receptor antagonist), LY302679, LY292025, LY307190, LY280263, LY289178, LY289525, LY294486 (AMPA/kainate antagonists) and LY382884 (an iGluR5 selective antagonist). Results obtained support a role for AMPA receptors in cerebral ischemia. LY377770 (a mixed AMPA/iGluR5 antagonist and active isomer of LY294486) demonstrated good neuroprotection with a 2-h time window and may therefore be useful in the treatment of ischaemic conditions.
在本研究中，我们评估了十氢异喹啉类化合物系列谷氨酸受体拮抗剂的体内外活性。使用配体与克隆的离子型谷氨酸受体2（iGluR2）和离子型谷氨酸受体5（iGluR5）结合，并通过皮质楔形标本中α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）和N-甲基-D-天冬氨酸（NMDA）诱发的反应，评估化合物对AMPA和海人藻酸受体的活性。在体内，通过大鼠脊髓标本和沙土鼠全脑缺血模型的电生理学方法检测化合物的拮抗剂活性。所测试的化合物有已证实在局灶性脑缺血模型中具有保护作用的LY293558、LY202157（一种NMDA拮抗剂）、LY246492（一种NMDA和AMPA受体拮抗剂）、LY302679、LY292025、LY307190、LY280263、LY289178、LY289525、LY294486（AMPA/海人藻酸拮抗剂）和LY382884（一种iGluR5选择性拮抗剂）。所得结果支持AMPA受体在脑缺血中起作用。LY377770（一种AMPA/iGluR5混合拮抗剂及LY294486的活性异构体）在2小时时间窗内显示出良好的神经保护作用，因此可能对缺血性疾病的治疗有用。
