Structure-activity relationships of pentacycloundecylamines at the N-methyl-D-aspartate receptor
Structure-activity relationships of pentacycloundecylamines at the N-methyl-D-aspartate receptor
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DOI：
10.1016/j.bmc.2006.09.060
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Van der Schvf, Cornelis J.
中科院分区：
文献类型：
--
作者：
Geldenhuys, Werner J.;Malan, Sarel F.;Van der Schvf, Cornelis J.
出于对具有多种作用机制的神经保护剂的兴趣，我们评估了一系列先前显示具有 L 型钙通道阻断活性和 N-甲基-D-天冬氨酸受体 (NMDAR) 拮抗活性的五环十一烷胺衍生物的结构-活性关系。我们利用功能测定法通过 Ca-45(2+) 流入突触神经体来测量 NMDAR 通道阻断。笼胺8-苄氨基-8,11-氧杂五环[5.4.0.0(2,6)。 0(3,10)。 0(5,9)]十一烷(NPG1-01)被证明是最有效的实验化合物，IC50为2.98 μM，而8-氨基-五环[5.4。 0.0(2.6)。 0(3,10)。 0(5,9)]十一烷具有第二强的IC50，为4.06μM。将NGP1-01的多环笼尺寸从五环十一烷增加到十三烷笼结构，但保留N-苄基部分，效力降低10倍，表明可容纳在通道结合位点中的笼体积的限制。在 NGP1-01 存在下，NMDA/甘氨酸诱导的最大 Ca-45(2+) 流入减弱 34%，对激动剂效力影响不显着。这些结果与这组化合物的非竞争性拮抗作用一致。 [H-3]MK-801 或 [H-3]TCP 放射性配体结合研究显示这些配体很少或没有被五环十一烷胺取代，这表明后一种化合物与 NMDAR 通道中的独特位点结合。测试的五环十一胺代表了一组新型 NMDAR 拮抗剂，具有作为神经退行性疾病（包括帕金森病和阿尔茨海默病）治疗剂的潜力。 (c) 2006 Elsevier Ltd. 保留所有权利。
Prompted by our interest in neuroprotective agents with multiple mechanisms of action, we assessed the structure-activity relationship of a series of pentacycloundecylamine derivatives previously shown to have both L-type calcium channel blocking activity and N-methyl-D-aspartate receptor (NMDAR) antagonistic activity. We utilized a functional assay to measure NMDAR channel block using Ca-45(2+) influx into synaptoneurosomes. The cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6). 0(3,10). 0(5,9)]undecane (NPG1-01) proved to be the most potent experimental compound with an IC50 of 2.98 mu M, while 8-amino-pentacyclo[5.4. 0.0(2.6). 0(3,10). 0(5,9)]undecane had the next most potent IC50 of 4.06 mu M. Increasing the polycyclic cage size of NGP1-01 from a pentacycloundecane to a tridecane cage structure, but retaining the N-benzyl moiety decreased potency 10-fold, indicating a limitation on the volume of the cage that can be accommodated in the channel binding site. In the presence of NGP1-01, NMDA/glycine-induced maximal Ca-45(2+) influx was attenuated by 34% with an insignificant effect on agonist potency. These results are consistent with uncompetitive antagonism for this group of compounds. Radioligand binding studies with [H-3]MK-801 or [H-3]TCP showed little or no displacement of these ligands by pentacycloundecylamines, suggesting that the latter compounds bind to a unique site in the NMDAR channel. The pentacycloundecylamines tested represent a novel group of NMDAR antagonists that have potential as therapeutic agents for neurodegenerative diseases including Parkinson's and Alzheimer's disease. (c) 2006 Elsevier Ltd. All rights reserved.