Hargreaves R J, Rigby M, Smith D, Hill R G, Iversen L L
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Neurochem Res. 1993 Dec;18(12):1263-9. doi: 10.1007/BF00975046.
The studies examined the effects of three antagonists (CPP, CGS 19755, and CGP 37849) that act competitively at the glutamate recognition site of the NMDA receptor complex on cortical neuronal morphology and cerebral limbic glucose metabolism. Responses were compared to the effects of dizocilpine, an uncompetitive NMDA receptor ion channel antagonist as a positive control. CGS 19755 and CGP 37849 (100 mg kg-1 i.p.) caused vacuolation in cortical pyramidal neurons in the posterior cingulate cortex four hours after dosing and this dose of CGP 37849 caused a pattern of limbic glucose metabolism activation similar to that seen after dizocilpine. CPP was without effect at 100 mg/kg i.p. probably due to poor brain penetration. The data indicates that the functional consequences (structural and metabolic) of NMDA receptor blockade with NMDA antagonists acting competitively at the glutamate recognition site and uncompetitively in the receptor ion channel are ultimately the same. Comparisons of the potential therapeutic window for CGS 19755 and CGP 37849 with dizocilpine (neuroprotection versus vacuolation) suggests that the window for the competitive antagonists is greater. This indicates that the potential therapeutic window for the different classes of NMDA antagonists may vary with the site in the receptor complex at which they interact.
这些研究考察了三种拮抗剂（CPP、CGS 19755和CGP 37849）的作用，它们在NMDA受体复合物的谷氨酸识别位点竞争性发挥作用，对皮质神经元形态和大脑边缘葡萄糖代谢产生影响。将这些反应与作为阳性对照的非竞争性NMDA受体离子通道拮抗剂地佐环平的作用进行了比较。给药后4小时，CGS 19755和CGP 37849（100 mg kg-1腹腔注射）导致后扣带回皮质的皮质锥体细胞出现空泡化，且该剂量的CGP 37849引起的边缘葡萄糖代谢激活模式与地佐环平给药后所见相似。腹腔注射100 mg/kg的CPP没有效果，可能是由于其脑渗透性差。数据表明，在谷氨酸识别位点竞争性发挥作用且在受体离子通道非竞争性发挥作用的NMDA拮抗剂阻断NMDA受体的功能后果（结构和代谢方面）最终是相同的。将CGS 19755和CGP 37849与地佐环平的潜在治疗窗（神经保护与空泡化）进行比较表明，竞争性拮抗剂的治疗窗更大。这表明不同类别的NMDA拮抗剂的潜在治疗窗可能因它们在受体复合物中相互作用的位点而异。
