Williams K, Romano C, Molinoff P B
Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia 19104-6084.
Mol Pharmacol. 1989 Oct;36(4):575-81.
A heat-stable factor of low molecular weight that increases the binding of [3H]MK-801 to rat brain membranes in the presence of maximally effective concentrations of L-glutamate and glycine was purified from bovine brain by reverse phase and ion-exchange high pressure liquid chromatography. The stimulatory activity was due to the presence of spermidine in the active fractions. Polyamines including spermine and spermidine are found in high concentrations in mammalian tissue. These compounds increase the affinity of N-methyl-D-aspartate (NMDA) receptors for [3H]MK-801 when assays are carried out in the presence of 100 microM L-glutamate and 100 microM glycine. At concentrations of 1 to 300 microM, a number of di- and triamines, including NH2(CH2)3NH2, NH2(CH2)3NH(CH2)2NH2, and NH2(CH2)3NH(CH2)3NH2, have partial or full agonist-like activity similar to that of spermidine. Other polyamines, including putrescine, cadaverine, NH2(CH2)2NH(CH2)2NH2, and CH3NH(CH2)3NHCH3, at concentrations of 1 to 100 microM, inhibited the binding of [3H]MK-801 in the presence of spermine, L-glutamate, and glycine but not in the presence of only L-glutamate and glycine. It is concluded that these compounds are selective antagonists of the effects of spermine at the NMDA receptor. These results suggest that there may be a polyamine recognition site on the NMDA receptor complex.
一种低分子量的热稳定因子，在L-谷氨酸和甘氨酸的最大有效浓度存在下，能增加[3H]MK-801与大鼠脑膜的结合，通过反相和离子交换高压液相色谱法从牛脑中纯化得到。刺激活性归因于活性组分中存在亚精胺。包括精胺和亚精胺在内的多胺在哺乳动物组织中浓度很高。当在100微摩尔/升L-谷氨酸和100微摩尔/升甘氨酸存在下进行测定时，这些化合物会增加N-甲基-D-天冬氨酸（NMDA）受体对[3H]MK-801的亲和力。在1至300微摩尔/升的浓度下，一些二胺和三胺，包括NH2(CH2)3NH2、NH2(CH2)3NH(CH2)2NH2和NH2(CH2)3NH(CH2)3NH2，具有与亚精胺相似的部分或完全激动剂样活性。其他多胺，包括腐胺、尸胺、NH2(CH2)2NH(CH2)2NH2和CH3NH(CH2)3NHCH3，在1至100微摩尔/升的浓度下，在精胺、L-谷氨酸和甘氨酸存在时抑制[3H]MK-801的结合，但仅在L-谷氨酸和甘氨酸存在时不抑制。得出的结论是，这些化合物是精胺在NMDA受体上作用的选择性拮抗剂。这些结果表明，NMDA受体复合物上可能存在一个多胺识别位点。
