Structural requirements for novel willardiine derivatives acting as AMPA and kainate receptor antagonists
Structural requirements for novel willardiine derivatives acting as AMPA and kainate receptor antagonists
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DOI：
10.1038/sj.bjp.0705148
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发表时间：
2003-03-01
影响因子：
7.3
通讯作者：
Jane, DE
中科院分区：
文献类型：
--
作者：
More, JCA;Troop, HM;Jane, DE
1天然产物Willardiine是AMPA受体激动剂。我们已经研究了所需的结构变化，以转换成拮抗剂在AMPA和红藻氨酸受体威拉地碱。进行了结构反应性分析，以发现结构。增加拮抗剂对AMPA或红藻氨酸受体的效力和/或选择性所需的特征。2背根诱发的腹根电位（fDR-VRP）的快分量的减少已用于研究AMPA受体拮抗剂活性。为了检查红藻氨酸受体的拮抗剂活性，评估了化合物抑制红藻氨酸诱导的背根纤维去极化的能力。3通过在N-3位添加甲基阻断尿嘧啶环的电离不足以将威拉地碱转化为拮抗剂。然而，具有在尿嘧啶环的N-3-位带有羧酸基团的侧链的维拉地碱衍生物可以拮抗AMPA和红藻氨酸受体。4S立体化学是最佳的拮抗作用。当比较具有不同酸间基团链长的化合物时，在带有羧基烷基侧链的系列化合物中，两个亚甲基的基团链长对于AMPA受体拮抗作用是优选的（UBP 275、UBP 277和UBP 279降低fDR-VRP，IC 50值分别为287 +/- 41、23.8 +/- 3.9和136 +/- 17 μ π ι）。对于红藻氨酸受体拮抗作用，两个或三个亚甲基基团几乎同样可接受（UBP 277和UBP 279降低背根红藻氨酸盐反应，表观K-D值为73.1 +/-4.5和60.5 +/-4.1 μ M，5在UBP 277和UBP 282的5-位添加碘基增强了对红藻氨酸受体的活性（UBP 291和UBP 301拮抗背根上的红藻氨酸盐反应，表观KD值分别为9.83 +/-1.62和5.94 +/-0.63 μ M）。6本研究中鉴定的最有用的拮抗剂是UBP 301，其是一种有效的和类似于30倍选择性红藻氨酸受体拮抗剂。UBP 282也可用于分离非GluR 5介导的红藻氨酸应答。英国药理学杂志（2003）138，1093-1100。doi：10. 1038/sj.bjp.705148
1 The natural product willardiine is an AMPA receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and kainate receptors. Structureactivity analysis has been carried out to discover the structural. features required to increase the potency and/or selectivity of the antagonists at AMPA or kainate receptors.2 Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA receptor antagonist activity. To examine antagonist activity at kainate receptors, the ability of compounds to depress kainate-induced depolarisations of dorsal root fibres was assessed.3 Blocking ionisation of the uracil ring by adding a methyl group to the N-3 position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N-3-position of the uracil ring could antagonise AMPA and kainate receptors.4 S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC50 values of 287 +/- 41, 23.8 +/- 3.9 and 136 +/- 17 pm, respectively). For kainate receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root kainate responses with apparent K-D values of 73.1 +/- 4.5 and 60.5 +/- 4.1 muM, respectively).5 Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at kainate receptors (UBP291 and UBP301 antagonised kainate responses on the dorsal root with apparent KD values of 9.83 +/- 1.62 and 5.94 +/- 0.63 muM, respectively).6 The most useful antagonist identified in this study was UBP301, which was a potent and similar to30-fold selective kainate receptor antagonist. UBP282 may also be of use in isolating a non-GluR5 -mediated kainate response. British Journal of Pharmacology (2003) 138, 1093-1100. doi: 10. 1038/sj.bjp.705148